Pub Date : 2025-11-05DOI: 10.1016/j.str.2025.10.009
Huifang Yan, Fengyun Ni, Qinghua Wang, Jianpeng Ma
Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme responsible for propionyl-CoA catabolism. Deficiencies in human PCC (hPCC) cause propionic acidemia, a severe metabolic disorder driven by toxic metabolite accumulation. Despite its therapeutic relevance, the structural basis of hPCC’s catalytic function remains unresolved. Here, we present high-resolution cryo-EM structures of hPCC in four distinct states, unliganded, ADP-, AMPPNP-, and ATP-bound/substrate-bound, capturing the full trajectory of the biotin carboxyl carrier protein (BCCP) domain as it translocates between active sites. Our results reinforce the crucial role of nucleotide-gated B-lid subdomain in synchronizing catalysis through coupling with BCCP movement. Structural and biochemical analysis of 10 disease-associated variants reveals how mutations disrupt key domain interfaces and dynamic motions required for activity. These new insights define the mechanistic principles governing hPCC functions, establish a structural framework for understanding PCC-related disorders, and lay the groundwork for future efforts to engineer functional replacements or modulators for metabolic therapy.
{"title":"Nanoscale conformational dynamics of human propionyl-CoA carboxylase","authors":"Huifang Yan, Fengyun Ni, Qinghua Wang, Jianpeng Ma","doi":"10.1016/j.str.2025.10.009","DOIUrl":"https://doi.org/10.1016/j.str.2025.10.009","url":null,"abstract":"Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme responsible for propionyl-CoA catabolism. Deficiencies in human PCC (hPCC) cause propionic acidemia, a severe metabolic disorder driven by toxic metabolite accumulation. Despite its therapeutic relevance, the structural basis of hPCC’s catalytic function remains unresolved. Here, we present high-resolution cryo-EM structures of hPCC in four distinct states, unliganded, ADP-, AMPPNP-, and ATP-bound/substrate-bound, capturing the full trajectory of the biotin carboxyl carrier protein (BCCP) domain as it translocates between active sites. Our results reinforce the crucial role of nucleotide-gated B-lid subdomain in synchronizing catalysis through coupling with BCCP movement. Structural and biochemical analysis of 10 disease-associated variants reveals how mutations disrupt key domain interfaces and dynamic motions required for activity. These new insights define the mechanistic principles governing hPCC functions, establish a structural framework for understanding PCC-related disorders, and lay the groundwork for future efforts to engineer functional replacements or modulators for metabolic therapy.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"28 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145442016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-05DOI: 10.1016/j.str.2025.10.010
Paula Wagner Egea, Florent Delhommel, Ghulam Mustafa, Florian Leiss-Maier, Lisa Klimper, Thomas Badmann, Anna Heider, Idoia Wille, Michael Groll, Michael Sattler, Cathleen Zeymer
Incorporating metal cofactors into computationally designed protein scaffolds provides a versatile route to novel protein functions, including the potential for new-to-nature enzyme catalysis. However, a major challenge in protein design is to understand how the scaffold architecture influences conformational dynamics. Here, we characterized structure and dynamics of a modular de novo scaffold with flexible inter-domain linkers. Three rationally engineered variants with different metal specificity were studied by combining X-ray crystallography, NMR spectroscopy, and molecular dynamics simulations. The lanthanide-binding variant was initially trapped in an inactive conformational state, which impaired efficient metal coordination and cerium-dependent photocatalytic activity. Stabilization of the active conformation by AI-guided sequence optimization using ProteinMPNN led to accelerated lanthanide binding and a 10-fold increase in kcat/Km for a photoenzymatic model reaction. Our results suggest that modular scaffold architectures provide an attractive starting point for de novo metalloenzyme engineering and that ProteinMPNN-based sequence redesign can stabilize desired conformational states.
{"title":"Modular protein scaffold architecture and AI-guided sequence optimization facilitate de novo metalloenzyme engineering","authors":"Paula Wagner Egea, Florent Delhommel, Ghulam Mustafa, Florian Leiss-Maier, Lisa Klimper, Thomas Badmann, Anna Heider, Idoia Wille, Michael Groll, Michael Sattler, Cathleen Zeymer","doi":"10.1016/j.str.2025.10.010","DOIUrl":"https://doi.org/10.1016/j.str.2025.10.010","url":null,"abstract":"Incorporating metal cofactors into computationally designed protein scaffolds provides a versatile route to novel protein functions, including the potential for new-to-nature enzyme catalysis. However, a major challenge in protein design is to understand how the scaffold architecture influences conformational dynamics. Here, we characterized structure and dynamics of a modular <em>de novo</em> scaffold with flexible inter-domain linkers. Three rationally engineered variants with different metal specificity were studied by combining X-ray crystallography, NMR spectroscopy, and molecular dynamics simulations. The lanthanide-binding variant was initially trapped in an inactive conformational state, which impaired efficient metal coordination and cerium-dependent photocatalytic activity. Stabilization of the active conformation by AI-guided sequence optimization using <em>ProteinMPNN</em> led to accelerated lanthanide binding and a 10-fold increase in k<sub>cat</sub>/K<sub>m</sub> for a photoenzymatic model reaction. Our results suggest that modular scaffold architectures provide an attractive starting point for <em>de novo</em> metalloenzyme engineering and that <em>ProteinMPNN</em>-based sequence redesign can stabilize desired conformational states.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"1 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145442012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-05DOI: 10.1016/j.str.2025.10.012
René L. Bærentsen, Kristina Kronborg, Ditlev E. Brodersen, Yong Everett Zhang
Insights into bacterial metabolic adaptation during stress is crucial for understanding early mechanisms of antibiotic resistance. In the Gram-negative bacterium Escherichia coli, the universal stringent response produces the alarmones (p)ppGpp that target many cellular proteins. The cellular nucleosidase PpnN is regulated by (p)ppGpp and was shown to balance bacterial fitness and persistence during fluoroquinolone exposure. pppGpp and ppGpp both activate PpnN, but differentially regulate its cooperativity via an unknown mechanism; furthermore, the catalytic mechanism of PpnN has remained unclear. Here, we provide mechanistic insights into the interaction of PpnN with a substrate analogue, reaction products, and alarmone molecules, which allows us to understand the catalytic mechanism of this family of nucleosidases and the differential modes of regulation by ppGpp and pppGpp, respectively. Comparison to the homologous plant cytokinin-producing LOG proteins reveals that PpnN utilizes an evolutionarily conserved purine hydrolysis mechanism, which in bacteria is regulated by alarmones during stress.
{"title":"Catalytic mechanism and differential alarmone regulation of a conserved stringent nucleosidase","authors":"René L. Bærentsen, Kristina Kronborg, Ditlev E. Brodersen, Yong Everett Zhang","doi":"10.1016/j.str.2025.10.012","DOIUrl":"https://doi.org/10.1016/j.str.2025.10.012","url":null,"abstract":"Insights into bacterial metabolic adaptation during stress is crucial for understanding early mechanisms of antibiotic resistance. In the Gram-negative bacterium <em>Escherichia coli</em>, the universal stringent response produces the alarmones (p)ppGpp that target many cellular proteins. The cellular nucleosidase PpnN is regulated by (p)ppGpp and was shown to balance bacterial fitness and persistence during fluoroquinolone exposure. pppGpp and ppGpp both activate PpnN, but differentially regulate its cooperativity via an unknown mechanism; furthermore, the catalytic mechanism of PpnN has remained unclear. Here, we provide mechanistic insights into the interaction of PpnN with a substrate analogue, reaction products, and alarmone molecules, which allows us to understand the catalytic mechanism of this family of nucleosidases and the differential modes of regulation by ppGpp and pppGpp, respectively. Comparison to the homologous plant cytokinin-producing LOG proteins reveals that PpnN utilizes an evolutionarily conserved purine hydrolysis mechanism, which in bacteria is regulated by alarmones during stress.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"28 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145442011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-05DOI: 10.1016/j.str.2025.10.011
Michael C. Newton-Vesty, Mariafrancesca Scalise, Sam A. Jamieson, Michael J. Currie, Hamish G. Brown, Sepideh Valimehr, Zachary D. Tillett, Kelsi R. Hall, Senwei Quan, Jane R. Allison, Andrew E. Whitten, Santosh Panjikar, Cesare Indiveri, Eric Hanssen, Peter D. Mace, Rachel A. North, Renwick C.J. Dobson, James S. Davies
Sulfate-reducing bacteria import organosulfur compounds from the environment for anaerobic respiration. They contribute to human disease and are problematic in industrial settings because they produce hydrogen sulfide. Here, we demonstrate how the sulfate-reducing bacterium Oleidesulfovibrio alaskensis imports isethionate, a common organosulfonate, using a tripartite ATP-independent periplasmic (TRAP) transporter (OaIsePQM). The cryo-EM structure of isethionate-bound OaIseQM to 2.98 Å resolution defines the substrate-binding site, two Na+-binding sites, and a distinct fusion helix. Key residues within the OaIseQM substrate-binding site are identified using substitution and proteoliposome assays. Functional studies demonstrate that OaIseQM requires the substrate-binding protein (OaIseP) and a Na+ gradient to drive transport. Modeling of the OaIsePQM complex supports that elevator-type conformational changes are involved in this unique coupled transport process. This work expands our knowledge of the transport of organosulfur compounds in bacteria and establishes OaIsePQM as a new model system for exploring the mechanism of TRAP transporters.
{"title":"Structural basis of isethionate transport by a TRAP transporter from a sulfate-reducing bacterium","authors":"Michael C. Newton-Vesty, Mariafrancesca Scalise, Sam A. Jamieson, Michael J. Currie, Hamish G. Brown, Sepideh Valimehr, Zachary D. Tillett, Kelsi R. Hall, Senwei Quan, Jane R. Allison, Andrew E. Whitten, Santosh Panjikar, Cesare Indiveri, Eric Hanssen, Peter D. Mace, Rachel A. North, Renwick C.J. Dobson, James S. Davies","doi":"10.1016/j.str.2025.10.011","DOIUrl":"https://doi.org/10.1016/j.str.2025.10.011","url":null,"abstract":"Sulfate-reducing bacteria import organosulfur compounds from the environment for anaerobic respiration. They contribute to human disease and are problematic in industrial settings because they produce hydrogen sulfide. Here, we demonstrate how the sulfate-reducing bacterium <em>Oleidesulfovibrio alaskensis</em> imports isethionate, a common organosulfonate, using a tripartite ATP-independent periplasmic (TRAP) transporter (<em>Oa</em>IsePQM). The cryo-EM structure of isethionate-bound <em>Oa</em>IseQM to 2.98 Å resolution defines the substrate-binding site, two Na<sup>+</sup>-binding sites, and a distinct fusion helix. Key residues within the <em>Oa</em>IseQM substrate-binding site are identified using substitution and proteoliposome assays. Functional studies demonstrate that <em>Oa</em>IseQM requires the substrate-binding protein (<em>Oa</em>IseP) and a Na<sup>+</sup> gradient to drive transport. Modeling of the <em>Oa</em>IsePQM complex supports that elevator-type conformational changes are involved in this unique coupled transport process. This work expands our knowledge of the transport of organosulfur compounds in bacteria and establishes <em>Oa</em>IsePQM as a new model system for exploring the mechanism of TRAP transporters.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"26 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145442015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-04DOI: 10.1016/j.str.2025.10.015
Mohan Babu, Jack F. Greenblatt, Andrew Emili, Natalie C.J. Strynadka, Reinhart A.F. Reithmeier, Trevor F. Moraes
No Abstract
没有抽象的
{"title":"Structure of a SLC26 Anion Transporter STAS Domain in Complex with Acyl Carrier Protein: Implications for E. coli YchM in Fatty Acid Metabolism","authors":"Mohan Babu, Jack F. Greenblatt, Andrew Emili, Natalie C.J. Strynadka, Reinhart A.F. Reithmeier, Trevor F. Moraes","doi":"10.1016/j.str.2025.10.015","DOIUrl":"https://doi.org/10.1016/j.str.2025.10.015","url":null,"abstract":"No Abstract","PeriodicalId":22168,"journal":{"name":"Structure","volume":"26 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145434682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-30DOI: 10.1016/j.str.2025.10.005
Yang Zhang, Zhe Zhang
{"title":"Structural basis of VAChT inhibition by spiroindolines and alkylsulfones","authors":"Yang Zhang, Zhe Zhang","doi":"10.1016/j.str.2025.10.005","DOIUrl":"https://doi.org/10.1016/j.str.2025.10.005","url":null,"abstract":"","PeriodicalId":22168,"journal":{"name":"Structure","volume":"354 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145396759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Structural basis of hydride and proton transfer reactions revealed by the detection of hydrogen atoms in mammalian NADH-cytochrome b5 reductase","authors":"Yu Hirano, Kazuo Kurihara, Katsuhiro Kusaka, Andreas Ostermann, Masahide Hikita, Shigenobu Kimura, Kunio Miki, Taro Tamada","doi":"10.1016/j.str.2025.10.006","DOIUrl":"https://doi.org/10.1016/j.str.2025.10.006","url":null,"abstract":"","PeriodicalId":22168,"journal":{"name":"Structure","volume":"151 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145396753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-28DOI: 10.1016/j.str.2025.10.004
Peixuan Yu, Bradon S. Krah, Melanie A. Orlando, Sundharraman Subramanian, Benjamin J. Orlando
Bacteria utilize a variety of mechanisms to remodel the cell wall in response to environmental and antimicrobial stress. In the model organism Bacillus subtilis, the ytr operon encoding putative ATP-binding cassette (ABC) transporter(s) is highly upregulated in response to cell wall-targeting antibiotics. Here we show that the ytr operon encodes two distinct ABC transporters: YtrBCD and YtrEF. Using cryo-electron microscopy(cryo-EM), we determined the structures of YtrEF in nucleotide-free and ADP-vanadate bound states. The structures demonstrate that YtrEF adopts a type VII ABC transporter fold. Nucleotide binding induced conformational changes that propagate from the cytosolic region through the transmembrane helices to ultimately reorient the extracellular domains. Extended bacterial growth assays and suppressor mutation identification indicated that YtrEF contributes to alteration of colony morphology. These findings establish YtrEF as a type VII ABC transporter that is induced by cell wall-targeting antibiotics and a new avenue to phenotypically assess the ytr operon.
{"title":"Structural analysis of a Gram-positive type VII ABC transporter induced by cell wall-targeting antibiotics","authors":"Peixuan Yu, Bradon S. Krah, Melanie A. Orlando, Sundharraman Subramanian, Benjamin J. Orlando","doi":"10.1016/j.str.2025.10.004","DOIUrl":"https://doi.org/10.1016/j.str.2025.10.004","url":null,"abstract":"Bacteria utilize a variety of mechanisms to remodel the cell wall in response to environmental and antimicrobial stress. In the model organism <em>Bacillus subtilis</em>, the <em>ytr</em> operon encoding putative ATP-binding cassette (ABC) transporter(s) is highly upregulated in response to cell wall-targeting antibiotics. Here we show that the <em>ytr</em> operon encodes two distinct ABC transporters: YtrBCD and YtrEF. Using cryo-electron microscopy(cryo-EM), we determined the structures of YtrEF in nucleotide-free and ADP-vanadate bound states. The structures demonstrate that YtrEF adopts a type VII ABC transporter fold. Nucleotide binding induced conformational changes that propagate from the cytosolic region through the transmembrane helices to ultimately reorient the extracellular domains. Extended bacterial growth assays and suppressor mutation identification indicated that YtrEF contributes to alteration of colony morphology. These findings establish YtrEF as a type VII ABC transporter that is induced by cell wall-targeting antibiotics and a new avenue to phenotypically assess the <em>ytr</em> operon.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"177 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145382148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-27DOI: 10.1016/j.str.2025.10.002
Yu Xu,Kaushik Thakkar,Li Guan,Yu Miao,Manal Mehibel,Robert B Lee,David Marciano,Vignesh Viswanathan,Ziwei Wang,Jinglong Wang,Lu Ji,Hongbin Cao,Camille Fisher Petrakian,Jocelyn Valenzuela,Edward LaGory,Xianglian Jia,Eui Jung Moon,Rodolph Martinez,Fang Wu,Richard L Frock,Everett J Moding,Quynh-Thu Le,Erinn B Rankin,Cheng Zhang,Possu Huang,Monica M Olcina,Amato J Giaccia,Edward E Graves
High-throughput mutagenesis approaches are widely employed to systematically characterize protein functions and play a critical role in therapeutic developments. As the largest class of membrane receptors, G protein-coupled receptors (GPCRs) are a primary focus of these studies. However, while significant progress has been made in understanding GPCRs themselves, mutagenesis studies on their ligands have lagged behind, because of the difficulties in solubilizing the target receptor. In this study, we present a novel approach that employs lipid vesicles to embed and stabilize target membrane receptors, allowing direct ligand screening. We applied this platform to investigate the anaphylatoxin complement 5a (C5a) and examined how mutations affect binding to its two native GPCRs: complement 5a receptor 1 (C5aR1) and complement 5a receptor 2 (C5aR2). The screening revealed new insights into the molecular basis of the interaction and led to the discovery of novel ligands that selectively activate C5aR2, but not C5aR1.
{"title":"High throughput mutational characterization of the GPCR ligand C5a using yeast display and deep sequencing.","authors":"Yu Xu,Kaushik Thakkar,Li Guan,Yu Miao,Manal Mehibel,Robert B Lee,David Marciano,Vignesh Viswanathan,Ziwei Wang,Jinglong Wang,Lu Ji,Hongbin Cao,Camille Fisher Petrakian,Jocelyn Valenzuela,Edward LaGory,Xianglian Jia,Eui Jung Moon,Rodolph Martinez,Fang Wu,Richard L Frock,Everett J Moding,Quynh-Thu Le,Erinn B Rankin,Cheng Zhang,Possu Huang,Monica M Olcina,Amato J Giaccia,Edward E Graves","doi":"10.1016/j.str.2025.10.002","DOIUrl":"https://doi.org/10.1016/j.str.2025.10.002","url":null,"abstract":"High-throughput mutagenesis approaches are widely employed to systematically characterize protein functions and play a critical role in therapeutic developments. As the largest class of membrane receptors, G protein-coupled receptors (GPCRs) are a primary focus of these studies. However, while significant progress has been made in understanding GPCRs themselves, mutagenesis studies on their ligands have lagged behind, because of the difficulties in solubilizing the target receptor. In this study, we present a novel approach that employs lipid vesicles to embed and stabilize target membrane receptors, allowing direct ligand screening. We applied this platform to investigate the anaphylatoxin complement 5a (C5a) and examined how mutations affect binding to its two native GPCRs: complement 5a receptor 1 (C5aR1) and complement 5a receptor 2 (C5aR2). The screening revealed new insights into the molecular basis of the interaction and led to the discovery of novel ligands that selectively activate C5aR2, but not C5aR1.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"7 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145380919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-24DOI: 10.1016/j.str.2025.09.011
Andrew D Huber,Efren Garcia-Maldonado,Wenwei Lin,Shyaron Poudel,Jing Wu,Darcie J Miller,Taosheng Chen
Nuclear receptor antagonists are used to treat various diseases, but the precise antagonist mechanisms differ among receptors and compounds. Understanding the interplay between ligand-receptor interactions and transcriptional outcomes is critical. The nuclear receptor pregnane X receptor (PXR) is activated by many medicinal compounds and upregulates drug metabolism genes in response, decreasing efficacy and/or increasing toxicity of drugs. Co-administered PXR antagonists could reduce these effects, but such compounds have only recently been identified, and molecular elements governing their actions remain largely unknown. Here, we show chemically similar PXR ligands with three distinct activities (agonist, antagonist, and inverse agonist) that are altered by PXR mutations. These diverging activities are linked to ligand-induced changes at the intersection of ligand, receptor ligand-binding pocket, and receptor surface where transcriptional coregulators are recruited. We also find that antagonists can act by multiple mechanisms regarding coregulator recruitment, highlighting the complexity of ligand-receptor interactions that influence transcriptional activity.
{"title":"Subtle changes in ligand-receptor interactions dramatically alter transcriptional outcomes of pregnane X receptor modulators.","authors":"Andrew D Huber,Efren Garcia-Maldonado,Wenwei Lin,Shyaron Poudel,Jing Wu,Darcie J Miller,Taosheng Chen","doi":"10.1016/j.str.2025.09.011","DOIUrl":"https://doi.org/10.1016/j.str.2025.09.011","url":null,"abstract":"Nuclear receptor antagonists are used to treat various diseases, but the precise antagonist mechanisms differ among receptors and compounds. Understanding the interplay between ligand-receptor interactions and transcriptional outcomes is critical. The nuclear receptor pregnane X receptor (PXR) is activated by many medicinal compounds and upregulates drug metabolism genes in response, decreasing efficacy and/or increasing toxicity of drugs. Co-administered PXR antagonists could reduce these effects, but such compounds have only recently been identified, and molecular elements governing their actions remain largely unknown. Here, we show chemically similar PXR ligands with three distinct activities (agonist, antagonist, and inverse agonist) that are altered by PXR mutations. These diverging activities are linked to ligand-induced changes at the intersection of ligand, receptor ligand-binding pocket, and receptor surface where transcriptional coregulators are recruited. We also find that antagonists can act by multiple mechanisms regarding coregulator recruitment, highlighting the complexity of ligand-receptor interactions that influence transcriptional activity.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"109 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145369499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：