Pub Date : 2024-05-06DOI: 10.1134/s0006297924040102
Mikhail Yu. Stepanichev, Diana I. Mamedova, Natalia V. Gulyaeva
Abstract
Data from clinical trials and animal experiments demonstrate relationship between chronic hypertension and development of cognitive impairments. Here, we review structural and biochemical alterations in the hippocampus of SHR rats with genetic hypertension, which are used as a model of essential hypertension and vascular dementia. In addition to hypertension, dysfunction of the hypothalamic-pituitary-adrenal system observed in SHR rats already at an early age may be a key factor of changes in the hippocampus at the structural and molecular levels. Global changes at the body level, such as hypertension and neurohumoral dysfunction, are associated with the development of vascular pathology and impairment of the blood-brain barrier. Changes in multiple biochemical glucocorticoid-dependent processes in the hippocampus, including dysfunction of steroid hormones receptors, impairments of neurotransmitter systems, BDNF deficiency, oxidative stress, and neuroinflammation are accompanied by the structural alterations, such as cellular signs of neuroinflammation micro- and astrogliosis, impairments of neurogenesis in the subgranular neurogenic zone, and neurodegenerative processes at the level of synapses, axons, and dendrites up to the death of neurons. The consequence of this is dysfunction of hippocampus, a key structure of the limbic system necessary for cognitive functions. Taking into account the available results at various levels starting from the body and brain structure (hippocampus) levels to molecular one, we can confirm translational validity of SHR rats for modeling mechanisms of vascular dementia.
{"title":"Hippocampus under Pressure: Molecular Mechanisms of Development of Cognitive Impairments in SHR Rats","authors":"Mikhail Yu. Stepanichev, Diana I. Mamedova, Natalia V. Gulyaeva","doi":"10.1134/s0006297924040102","DOIUrl":"https://doi.org/10.1134/s0006297924040102","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Abstract</h3><p>Data from clinical trials and animal experiments demonstrate relationship between chronic hypertension and development of cognitive impairments. Here, we review structural and biochemical alterations in the hippocampus of SHR rats with genetic hypertension, which are used as a model of essential hypertension and vascular dementia. In addition to hypertension, dysfunction of the hypothalamic-pituitary-adrenal system observed in SHR rats already at an early age may be a key factor of changes in the hippocampus at the structural and molecular levels. Global changes at the body level, such as hypertension and neurohumoral dysfunction, are associated with the development of vascular pathology and impairment of the blood-brain barrier. Changes in multiple biochemical glucocorticoid-dependent processes in the hippocampus, including dysfunction of steroid hormones receptors, impairments of neurotransmitter systems, BDNF deficiency, oxidative stress, and neuroinflammation are accompanied by the structural alterations, such as cellular signs of neuroinflammation micro- and astrogliosis, impairments of neurogenesis in the subgranular neurogenic zone, and neurodegenerative processes at the level of synapses, axons, and dendrites up to the death of neurons. The consequence of this is dysfunction of hippocampus, a key structure of the limbic system necessary for cognitive functions. Taking into account the available results at various levels starting from the body and brain structure (hippocampus) levels to molecular one, we can confirm translational validity of SHR rats for modeling mechanisms of vascular dementia.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140883903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-06DOI: 10.1134/s0006297924040096
Yulia V. Bertsova, Marina V. Serebryakova, Vladimir A. Bogachev, Alexander A. Baykov, Alexander V. Bogachev
Abstract
Many microorganisms are capable of anaerobic respiration in the absence of oxygen, by using different organic compounds as terminal acceptors in electron transport chain. We identify here an anaerobic respiratory chain protein responsible for acrylate reduction in the marine bacterium Shewanella woodyi. When the periplasmic proteins of S. woodyi were separated by ion exchange chromatography, acrylate reductase activity copurified with an ArdA protein (Swoo_0275). Heterologous expression of S. woodyiardA gene (swoo_0275) in Shewanella oneidensis MR-1 cells did not result in the appearance in them of periplasmic acrylate reductase activity, but such activity was detected when the ardA gene was co-expressed with an ardB gene (swoo_0276). Together, these genes encode flavocytochrome c ArdAB, which is thus responsible for acrylate reduction in S. woodyi cells. ArdAB was highly specific for acrylate as substrate and reduced only methacrylate (at a 22-fold lower rate) among a series of other tested 2-enoates. In line with these findings, acrylate and methacrylate induced ardA gene expression in S. woodyi under anaerobic conditions, which was accompanied by the appearance of periplasmic acrylate reductase activity. ArdAB-linked acrylate reduction supports dimethylsulfoniopropionate-dependent anaerobic respiration in S. woodyi and, possibly, other marine bacteria.
{"title":"Acrylate Reductase of an Anaerobic Electron Transport Chain of the Marine Bacterium Shewanella woodyi","authors":"Yulia V. Bertsova, Marina V. Serebryakova, Vladimir A. Bogachev, Alexander A. Baykov, Alexander V. Bogachev","doi":"10.1134/s0006297924040096","DOIUrl":"https://doi.org/10.1134/s0006297924040096","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Abstract</h3><p>Many microorganisms are capable of anaerobic respiration in the absence of oxygen, by using different organic compounds as terminal acceptors in electron transport chain. We identify here an anaerobic respiratory chain protein responsible for acrylate reduction in the marine bacterium <i>Shewanella woodyi</i>. When the periplasmic proteins of <i>S. woodyi</i> were separated by ion exchange chromatography, acrylate reductase activity copurified with an ArdA protein (Swoo_0275). Heterologous expression of <i>S. woodyi</i> <i>ard</i>A gene (<i>swoo</i>_0275) in <i>Shewanella oneidensis</i> MR-1 cells did not result in the appearance in them of periplasmic acrylate reductase activity, but such activity was detected when the <i>ard</i>A gene was co-expressed with an <i>ard</i>B gene (<i>swoo</i>_0276). Together, these genes encode flavocytochrome <i>c</i> ArdAB, which is thus responsible for acrylate reduction in <i>S. woodyi</i> cells. ArdAB was highly specific for acrylate as substrate and reduced only methacrylate (at a 22-fold lower rate) among a series of other tested 2-enoates. In line with these findings, acrylate and methacrylate induced <i>ard</i>A gene expression in <i>S. woodyi</i> under anaerobic conditions, which was accompanied by the appearance of periplasmic acrylate reductase activity. ArdAB-linked acrylate reduction supports dimethylsulfoniopropionate-dependent anaerobic respiration in <i>S. woodyi</i> and, possibly, other marine bacteria.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140883812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-06DOI: 10.1134/s0006297924040126
Mikhail Raevskiy, Maxim Sorokin, Aleksandra Emelianova, Galina Zakharova, Elena Poddubskaya, Marianna Zolotovskaia, Anton Buzdin
Abstract
Identification of genes and molecular pathways with congruent profiles in the proteomic and transcriptomic datasets may result in the discovery of promising transcriptomic biomarkers that would be more relevant to phenotypic changes. In this study, we conducted comparative analysis of 943 paired RNA and proteomic profiles obtained for the same samples of seven human cancer types from The Cancer Genome Atlas (TCGA) and NCI Clinical Proteomic Tumor Analysis Consortium (CPTAC) [two major open human cancer proteomic and transcriptomic databases] that included 15,112 protein-coding genes and 1611 molecular pathways. Overall, our findings demonstrated statistically significant improvement of the congruence between RNA and proteomic profiles when performing analysis at the level of molecular pathways rather than at the level of individual gene products. Transition to the molecular pathway level of data analysis increased the correlation to 0.19-0.57 (Pearson) and 0.14-057 (Spearman), or 2-3-fold for some cancer types. Evaluating the gain of the correlation upon transition to the data analysis the pathway level can be used to refine the omics data by identifying outliers that can be excluded from the comparison of RNA and proteomic profiles. We suggest using sample- and gene-wise correlations for individual genes and molecular pathways as a measure of quality of RNA/protein paired molecular data. We also provide a database of human genes, molecular pathways, and samples related to the correlation between RNA and protein products to facilitate an exploration of new cancer transcriptomic biomarkers and molecular mechanisms at different levels of human gene expression.
{"title":"Sample-Wise and Gene-Wise Comparisons Confirm a Greater Similarity of RNA and Protein Expression Data at the Level of Molecular Pathways and Suggest an Approach for the Data Quality Check in High-Throughput Expression Databases","authors":"Mikhail Raevskiy, Maxim Sorokin, Aleksandra Emelianova, Galina Zakharova, Elena Poddubskaya, Marianna Zolotovskaia, Anton Buzdin","doi":"10.1134/s0006297924040126","DOIUrl":"https://doi.org/10.1134/s0006297924040126","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Abstract</h3><p>Identification of genes and molecular pathways with congruent profiles in the proteomic and transcriptomic datasets may result in the discovery of promising transcriptomic biomarkers that would be more relevant to phenotypic changes. In this study, we conducted comparative analysis of 943 paired RNA and proteomic profiles obtained for the same samples of seven human cancer types from The Cancer Genome Atlas (TCGA) and NCI Clinical Proteomic Tumor Analysis Consortium (CPTAC) [two major open human cancer proteomic and transcriptomic databases] that included 15,112 protein-coding genes and 1611 molecular pathways. Overall, our findings demonstrated statistically significant improvement of the congruence between RNA and proteomic profiles when performing analysis at the level of molecular pathways rather than at the level of individual gene products. Transition to the molecular pathway level of data analysis increased the correlation to 0.19-0.57 (Pearson) and 0.14-057 (Spearman), or 2-3-fold for some cancer types. Evaluating the gain of the correlation upon transition to the data analysis the pathway level can be used to refine the omics data by identifying outliers that can be excluded from the comparison of RNA and proteomic profiles. We suggest using sample- and gene-wise correlations for individual genes and molecular pathways as a measure of quality of RNA/protein paired molecular data. We also provide a database of human genes, molecular pathways, and samples related to the correlation between RNA and protein products to facilitate an exploration of new cancer transcriptomic biomarkers and molecular mechanisms at different levels of human gene expression.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140884020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-06DOI: 10.1134/s0006297924040060
Evgeniya A. Tikhonova, Pavel G. Georgiev, Oksana G. Maksimenko
Abstract
Dosage compensation complex (DCC), which consists of five proteins and two non-coding RNAs roX, specifically binds to the X chromosome in males, providing a higher level of gene expression necessary to compensate for the monosomy of the sex chromosome in male Drosophila compared to the two X chromosomes in females. The MSL2 protein contains the N-terminal RING domain, which acts as an E3 ligase in ubiquitination of proteins and is the only subunit of the complex expressed only in males. Functional role of the two C-terminal domains of the MSL2 protein, enriched with proline (P-domain) and basic amino acids (B-domain), was investigated. As a result, it was shown that the B-domain destabilizes the MSL2 protein, which is associated with the presence of two lysines ubiquitination of which is under control of the RING domain of MSL2. The unstructured proline-rich domain stimulates transcription of the roX2 gene, which is necessary for effective formation of the dosage compensation complex.
摘要剂量补偿复合体（DCC）由5个蛋白质和2个非编码RNA roX组成，特异性地与雄性果蝇的X染色体结合，与雌性果蝇的两条X染色体相比，DCC提供了更高水平的基因表达，以补偿雄性果蝇性染色体的单体性。MSL2 蛋白含有 N 端 RING 结构域，该结构域在蛋白质泛素化过程中起 E3 连接酶的作用，是该复合体中仅在雄性果蝇中表达的唯一亚基。研究人员对富含脯氨酸（P-domain）和碱性氨基酸（B-domain）的 MSL2 蛋白的两个 C 端结构域的功能作用进行了研究。结果表明，B-结构域会破坏 MSL2 蛋白的稳定性，这与 MSL2 的 RING 结构域控制两个赖氨酸泛素化有关。非结构化富脯氨酸结构域刺激了roX2基因的转录，而roX2基因是有效形成剂量补偿复合物的必要条件。
{"title":"Functional Role of C-terminal Domains in the MSL2 Protein of Drosophila melanogaster","authors":"Evgeniya A. Tikhonova, Pavel G. Georgiev, Oksana G. Maksimenko","doi":"10.1134/s0006297924040060","DOIUrl":"https://doi.org/10.1134/s0006297924040060","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Abstract</h3><p>Dosage compensation complex (DCC), which consists of five proteins and two non-coding RNAs <i>roX</i>, specifically binds to the X chromosome in males, providing a higher level of gene expression necessary to compensate for the monosomy of the sex chromosome in male <i>Drosophila</i> compared to the two X chromosomes in females. The MSL2 protein contains the N-terminal RING domain, which acts as an E3 ligase in ubiquitination of proteins and is the only subunit of the complex expressed only in males. Functional role of the two C-terminal domains of the MSL2 protein, enriched with proline (P-domain) and basic amino acids (B-domain), was investigated. As a result, it was shown that the B-domain destabilizes the MSL2 protein, which is associated with the presence of two lysines ubiquitination of which is under control of the RING domain of MSL2. The unstructured proline-rich domain stimulates transcription of the <i>roX2</i> gene, which is necessary for effective formation of the dosage compensation complex.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140883761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-06DOI: 10.1134/s0006297924040084
Anna A. Valyaeva, Eugene V. Sheval
Abstract
Eukaryotic cells are characterized by a high degree of compartmentalization of their internal contents, which ensures precise and controlled regulation of intracellular processes. During many processes, including different stages of transcription, dynamic membraneless compartments termed biomolecular condensates are formed. Transcription condensates contain various transcription factors and RNA polymerase and are formed by high- and low-specificity interactions between the proteins, DNA, and nearby RNA. This review discusses recent data demonstrating important role of nonspecific multivalent protein–protein and RNA–protein interactions in organization and regulation of transcription.
{"title":"Nonspecific Interactions in Transcription Regulation and Organization of Transcriptional Condensates","authors":"Anna A. Valyaeva, Eugene V. Sheval","doi":"10.1134/s0006297924040084","DOIUrl":"https://doi.org/10.1134/s0006297924040084","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Abstract</h3><p>Eukaryotic cells are characterized by a high degree of compartmentalization of their internal contents, which ensures precise and controlled regulation of intracellular processes. During many processes, including different stages of transcription, dynamic membraneless compartments termed biomolecular condensates are formed. Transcription condensates contain various transcription factors and RNA polymerase and are formed by high- and low-specificity interactions between the proteins, DNA, and nearby RNA. This review discusses recent data demonstrating important role of nonspecific multivalent protein–protein and RNA–protein interactions in organization and regulation of transcription.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140883973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-06DOI: 10.1134/s0006297924040011
Arkadiy K. Golov, Alexey A. Gavrilov
Abstract
Accurate duplication and separation of long linear genomic DNA molecules is associated with a number of purely mechanical problems. SMC complexes are key components of the cellular machinery that ensures decatenation of sister chromosomes and compaction of genomic DNA during division. Cohesin, one of the essential eukaryotic SMC complexes, has a typical ring structure with intersubunit pore through which DNA molecules can be threaded. Capacity of cohesin for such topological entrapment of DNA is crucial for the phenomenon of post-replicative association of sister chromatids better known as cohesion. Recently, it became apparent that cohesin and other SMC complexes are, in fact, motor proteins with a very peculiar movement pattern leading to formation of DNA loops. This specific process has been called loop extrusion. Extrusion underlies multiple functions of cohesin beyond cohesion, but molecular mechanism of the process remains a mystery. In this review, we summarized the data on molecular architecture of cohesin, effect of ATP hydrolysis cycle on this architecture, and known modes of cohesin–DNA interactions. Many of the seemingly disparate facts presented here will probably be incorporated in a unified mechanistic model of loop extrusion in the not-so-distant future.
摘要 长线性基因组 DNA 分子的精确复制和分离与许多纯机械问题有关。SMC复合物是细胞机械的关键组成部分，可在分裂过程中确保姐妹染色体的分离和基因组DNA的压实。聚合素是真核生物 SMC 复合物的重要组成部分之一，具有典型的环状结构，其亚基间有孔隙，DNA 分子可穿过孔隙。粘合素对 DNA 的这种拓扑夹持能力对于姐妹染色单体复制后的结合现象至关重要，这种结合也被称为内聚。最近，人们发现，粘合素和其他 SMC 复合物实际上是一种运动蛋白，其运动模式非常奇特，可导致 DNA 环的形成。这一特殊过程被称为环挤压。挤压是凝聚素除内聚之外的多种功能的基础，但这一过程的分子机制仍是一个谜。在这篇综述中，我们总结了有关凝聚素分子结构、ATP水解循环对该结构的影响以及凝聚素-DNA相互作用已知模式的数据。在不远的将来，这里介绍的许多看似互不相关的事实很可能会被纳入一个统一的环挤压机理模型中。
{"title":"Cohesin Complex: Structure and Principles of Interaction with DNA","authors":"Arkadiy K. Golov, Alexey A. Gavrilov","doi":"10.1134/s0006297924040011","DOIUrl":"https://doi.org/10.1134/s0006297924040011","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Abstract</h3><p>Accurate duplication and separation of long linear genomic DNA molecules is associated with a number of purely mechanical problems. SMC complexes are key components of the cellular machinery that ensures decatenation of sister chromosomes and compaction of genomic DNA during division. Cohesin, one of the essential eukaryotic SMC complexes, has a typical ring structure with intersubunit pore through which DNA molecules can be threaded. Capacity of cohesin for such topological entrapment of DNA is crucial for the phenomenon of post-replicative association of sister chromatids better known as cohesion. Recently, it became apparent that cohesin and other SMC complexes are, in fact, motor proteins with a very peculiar movement pattern leading to formation of DNA loops. This specific process has been called loop extrusion. Extrusion underlies multiple functions of cohesin beyond cohesion, but molecular mechanism of the process remains a mystery. In this review, we summarized the data on molecular architecture of cohesin, effect of ATP hydrolysis cycle on this architecture, and known modes of cohesin–DNA interactions. Many of the seemingly disparate facts presented here will probably be incorporated in a unified mechanistic model of loop extrusion in the not-so-distant future.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140886464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-06DOI: 10.1134/s0006297924040138
Polina A. Khorn, Aleksandra P. Luginina, Vladimir A. Pospelov, Dmitrii E. Dashevsky, Andrey N. Khnykin, Olga V. Moiseeva, Nadezhda A. Safronova, Anatolii S. Belousov, Alexey V. Mishin, Valentin I. Borshchevsky
Abstract
G protein-coupled receptors (GPCRs) play a key role in the transduction of extracellular signals to cells and regulation of many biological processes, which makes these membrane proteins one of the most important targets for pharmacological agents. A significant increase in the number of resolved atomic structures of GPCRs has opened the possibility of developing pharmaceuticals targeting these receptors via structure-based drug design (SBDD). SBDD employs information on the structure of receptor–ligand complexes to search for selective ligands without the need for an extensive high-throughput experimental ligand screening and can significantly expand the chemical space for ligand search. In this review, we describe the process of deciphering GPCR structures using X-ray diffraction analysis and cryoelectron microscopy as an important stage in the rational design of drugs targeting this receptor class. Our main goal was to present modern developments and key features of experimental methods used in SBDD of GPCR-targeting agents to a wide range of specialists.
{"title":"Rational Design of Drugs Targeting G-Protein-Coupled Receptors: A Structural Biology Perspective","authors":"Polina A. Khorn, Aleksandra P. Luginina, Vladimir A. Pospelov, Dmitrii E. Dashevsky, Andrey N. Khnykin, Olga V. Moiseeva, Nadezhda A. Safronova, Anatolii S. Belousov, Alexey V. Mishin, Valentin I. Borshchevsky","doi":"10.1134/s0006297924040138","DOIUrl":"https://doi.org/10.1134/s0006297924040138","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Abstract</h3><p>G protein-coupled receptors (GPCRs) play a key role in the transduction of extracellular signals to cells and regulation of many biological processes, which makes these membrane proteins one of the most important targets for pharmacological agents. A significant increase in the number of resolved atomic structures of GPCRs has opened the possibility of developing pharmaceuticals targeting these receptors via structure-based drug design (SBDD). SBDD employs information on the structure of receptor–ligand complexes to search for selective ligands without the need for an extensive high-throughput experimental ligand screening and can significantly expand the chemical space for ligand search. In this review, we describe the process of deciphering GPCR structures using X-ray diffraction analysis and cryoelectron microscopy as an important stage in the rational design of drugs targeting this receptor class. Our main goal was to present modern developments and key features of experimental methods used in SBDD of GPCR-targeting agents to a wide range of specialists.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140883970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-06DOI: 10.1134/s0006297924040047
Maria M. Gridina, Yana K. Stepanchuk, Miroslav A. Nurridinov, Timofey A. Lagunov, Nikita Yu. Torgunakov, Artem A. Shadsky, Anastasia I. Ryabova, Nikolay V. Vasiliev, Sergey V. Vtorushin, Tatyana S. Gerashchenko, Evgeny V. Denisov, Mikhail A. Travin, Maxim A. Korolev, Veniamin S. Fishman
Abstract
Molecular genetic analysis of tumor tissues is the most important step towards understanding the mechanisms of cancer development; it is also necessary for the choice of targeted therapy. The Hi-C (high-throughput chromatin conformation capture) technology can be used to detect various types of genomic variants, including balanced chromosomal rearrangements, such as inversions and translocations. We propose a modification of the Hi-C method for the analysis of chromatin contacts in formalin-fixed paraffin-embedded (FFPE) sections of tumor tissues. The developed protocol allows to generate high-quality Hi-C data and detect all types of chromosomal rearrangements. We have analyzed various databases to compile a comprehensive list of translocations that hold clinical importance for the targeted therapy selection. The practical value of molecular genetic testing is its ability to influence the treatment strategies and to provide prognostic insights. Detecting specific chromosomal rearrangements can guide the choice of the targeted therapies, which is a critical aspect of personalized medicine in oncology.
{"title":"Modification of the Hi-C Technology for Molecular Genetic Analysis of Formalin-Fixed Paraffin-Embedded Sections of Tumor Tissues","authors":"Maria M. Gridina, Yana K. Stepanchuk, Miroslav A. Nurridinov, Timofey A. Lagunov, Nikita Yu. Torgunakov, Artem A. Shadsky, Anastasia I. Ryabova, Nikolay V. Vasiliev, Sergey V. Vtorushin, Tatyana S. Gerashchenko, Evgeny V. Denisov, Mikhail A. Travin, Maxim A. Korolev, Veniamin S. Fishman","doi":"10.1134/s0006297924040047","DOIUrl":"https://doi.org/10.1134/s0006297924040047","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Abstract</h3><p>Molecular genetic analysis of tumor tissues is the most important step towards understanding the mechanisms of cancer development; it is also necessary for the choice of targeted therapy. The Hi-C (high-throughput chromatin conformation capture) technology can be used to detect various types of genomic variants, including balanced chromosomal rearrangements, such as inversions and translocations. We propose a modification of the Hi-C method for the analysis of chromatin contacts in formalin-fixed paraffin-embedded (FFPE) sections of tumor tissues. The developed protocol allows to generate high-quality Hi-C data and detect all types of chromosomal rearrangements. We have analyzed various databases to compile a comprehensive list of translocations that hold clinical importance for the targeted therapy selection. The practical value of molecular genetic testing is its ability to influence the treatment strategies and to provide prognostic insights. Detecting specific chromosomal rearrangements can guide the choice of the targeted therapies, which is a critical aspect of personalized medicine in oncology.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140886320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-06DOI: 10.1134/s0006297924040114
Irina B. Alieva, Anton S. Shakhov, Alexander A. Dayal, Aleksandra S. Churkina, Olga I. Parfenteva, Alexander A. Minin
Abstract
Intermediate filaments (IFs), being traditionally the least studied component of the cytoskeleton, have begun to receive more attention in recent years. IFs are found in different cell types and are specific to them. Accumulated data have shifted the paradigm about the role of IFs as structures that merely provide mechanical strength to the cell. In addition to this role, IFs have been shown to participate in maintaining cell shape and strengthening cell adhesion. The data have also been obtained that point out to the role of IFs in a number of other biological processes, including organization of microtubules and microfilaments, regulation of nuclear structure and activity, cell cycle control, and regulation of signal transduction pathways. They are also actively involved in the regulation of several aspects of intracellular transport. Among the intermediate filament proteins, vimentin is of particular interest for researchers. Vimentin has been shown to be associated with a range of diseases, including cancer, cataracts, Crohn’s disease, rheumatoid arthritis, and HIV. In this review, we focus almost exclusively on vimentin and the currently known functions of vimentin intermediate filaments (VIFs). This is due to the structural features of vimentin, biological functions of its domains, and its involvement in the regulation of a wide range of basic cellular functions, and its role in the development of human diseases. Particular attention in the review will be paid to comparing the role of VIFs with the role of intermediate filaments consisting of other proteins in cell physiology.
摘要中间丝（IFs）历来是细胞骨架中研究最少的成分，近年来开始受到越来越多的关注。中间丝存在于不同类型的细胞中，并具有特异性。积累的数据已经改变了 IF 的作用模式，即 IF 只是为细胞提供机械强度的结构。除这一作用外，IFs 还参与维持细胞形状和加强细胞粘附力。还有数据表明，IFs 还在其他一些生物过程中发挥作用，包括微管和微丝的组织、核结构和核活动的调控、细胞周期的控制以及信号转导途径的调控。它们还积极参与调节细胞内运输的多个方面。在中间丝蛋白中，研究人员对波形蛋白尤其感兴趣。研究表明，波形蛋白与一系列疾病有关，包括癌症、白内障、克罗恩病、类风湿性关节炎和艾滋病。在这篇综述中，我们几乎只关注波形蛋白和目前已知的波形蛋白中间丝（VIF）的功能。这是由于波形蛋白的结构特征、其结构域的生物学功能、参与调控广泛的基本细胞功能以及在人类疾病发展中的作用。本综述将特别关注将 VIF 的作用与由其他蛋白质组成的中间丝在细胞生理学中的作用进行比较。
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Pub Date : 2024-05-06DOI: 10.1134/s0006297924040035
Larisa S. Melnikova, Varvara V. Molodina, Pavel G. Georgiev, Anton K. Golovnin
Abstract
Su(Hw) belongs to the class of proteins that organize chromosome architecture, determine promoter activity, and participate in formation of the boundaries/insulators between the regulatory domains. This protein contains a cluster of 12 zinc fingers of the C2H2 type, some of which are responsible for binding to the consensus site. The Su(Hw) protein forms complex with the Mod(mdg4)-67.2 and the CP190 proteins, where the last one binds to all known Drosophila insulators. To further study functioning of the Su(Hw)-dependent complexes, we used the previously described su(Hw)E8 mutation with inactive seventh zinc finger, which produces mutant protein that cannot bind to the consensus site. The present work shows that the Su(Hw)E8 protein continues to directly interact with the CP190 and Mod(mdg4)-67.2 proteins. Through interaction with Mod(mdg4)-67.2, the Su(Hw)E8 protein can be recruited into the Su(Hw)-dependent complexes formed on chromatin and enhance their insulator activity. Our results demonstrate that the Su(Hw) dependent complexes without bound DNA can be recruited to the Su(Hw) binding sites through the specific protein–protein interactions that are stabilized by Mod(mdg4)-67.2.
{"title":"Role of Mod(mdg4)-67.2 Protein in Interactions between Su(Hw)-Dependent Complexes and Their Recruitment to Chromatin","authors":"Larisa S. Melnikova, Varvara V. Molodina, Pavel G. Georgiev, Anton K. Golovnin","doi":"10.1134/s0006297924040035","DOIUrl":"https://doi.org/10.1134/s0006297924040035","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Abstract</h3><p>Su(Hw) belongs to the class of proteins that organize chromosome architecture, determine promoter activity, and participate in formation of the boundaries/insulators between the regulatory domains. This protein contains a cluster of 12 zinc fingers of the C2H2 type, some of which are responsible for binding to the consensus site. The Su(Hw) protein forms complex with the Mod(mdg4)-67.2 and the CP190 proteins, where the last one binds to all known <i>Drosophila</i> insulators. To further study functioning of the Su(Hw)-dependent complexes, we used the previously described <i>su(Hw)</i><sup>E8</sup> mutation with inactive seventh zinc finger, which produces mutant protein that cannot bind to the consensus site. The present work shows that the Su(Hw)<sup>E8</sup> protein continues to directly interact with the CP190 and Mod(mdg4)-67.2 proteins. Through interaction with Mod(mdg4)-67.2, the Su(Hw)<sup>E8</sup> protein can be recruited into the Su(Hw)-dependent complexes formed on chromatin and enhance their insulator activity. Our results demonstrate that the Su(Hw) dependent complexes without bound DNA can be recruited to the Su(Hw) binding sites through the specific protein–protein interactions that are stabilized by Mod(mdg4)-67.2.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140886431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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