Pub Date : 2024-05-09DOI: 10.1038/s41594-024-01288-5
Erin C. Yang, Robby Divine, Marcos C. Miranda, Andrew J. Borst, Will Sheffler, Jason Z. Zhang, Justin Decarreau, Amijai Saragovi, Mohamad Abedi, Nicolas Goldbach, Maggie Ahlrichs, Craig Dobbins, Alexis Hand, Suna Cheng, Mila Lamb, Paul M. Levine, Sidney Chan, Rebecca Skotheim, Jorge Fallas, George Ueda, Joshua Lubner, Masaharu Somiya, Alena Khmelinskaia, Neil P. King, David Baker
Programming protein nanomaterials to respond to changes in environmental conditions is a current challenge for protein design and is important for targeted delivery of biologics. Here we describe the design of octahedral non-porous nanoparticles with a targeting antibody on the two-fold symmetry axis, a designed trimer programmed to disassemble below a tunable pH transition point on the three-fold axis, and a designed tetramer on the four-fold symmetry axis. Designed non-covalent interfaces guide cooperative nanoparticle assembly from independently purified components, and a cryo-EM density map closely matches the computational design model. The designed nanoparticles can package protein and nucleic acid payloads, are endocytosed following antibody-mediated targeting of cell surface receptors, and undergo tunable pH-dependent disassembly at pH values ranging between 5.9 and 6.7. The ability to incorporate almost any antibody into a non-porous pH-dependent nanoparticle opens up new routes to antibody-directed targeted delivery. Designed novel protein nanoparticle technology integrates antibody targeting and responds to changes in environmental conditions to release protected molecular cargoes, opening new applications for precision medicine.
{"title":"Computational design of non-porous pH-responsive antibody nanoparticles","authors":"Erin C. Yang, Robby Divine, Marcos C. Miranda, Andrew J. Borst, Will Sheffler, Jason Z. Zhang, Justin Decarreau, Amijai Saragovi, Mohamad Abedi, Nicolas Goldbach, Maggie Ahlrichs, Craig Dobbins, Alexis Hand, Suna Cheng, Mila Lamb, Paul M. Levine, Sidney Chan, Rebecca Skotheim, Jorge Fallas, George Ueda, Joshua Lubner, Masaharu Somiya, Alena Khmelinskaia, Neil P. King, David Baker","doi":"10.1038/s41594-024-01288-5","DOIUrl":"10.1038/s41594-024-01288-5","url":null,"abstract":"Programming protein nanomaterials to respond to changes in environmental conditions is a current challenge for protein design and is important for targeted delivery of biologics. Here we describe the design of octahedral non-porous nanoparticles with a targeting antibody on the two-fold symmetry axis, a designed trimer programmed to disassemble below a tunable pH transition point on the three-fold axis, and a designed tetramer on the four-fold symmetry axis. Designed non-covalent interfaces guide cooperative nanoparticle assembly from independently purified components, and a cryo-EM density map closely matches the computational design model. The designed nanoparticles can package protein and nucleic acid payloads, are endocytosed following antibody-mediated targeting of cell surface receptors, and undergo tunable pH-dependent disassembly at pH values ranging between 5.9 and 6.7. The ability to incorporate almost any antibody into a non-porous pH-dependent nanoparticle opens up new routes to antibody-directed targeted delivery. Designed novel protein nanoparticle technology integrates antibody targeting and responds to changes in environmental conditions to release protected molecular cargoes, opening new applications for precision medicine.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 9","pages":"1404-1412"},"PeriodicalIF":12.5,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01288-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140895556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-09DOI: 10.1038/s41594-024-01289-4
Targeted biologics delivery requires programming multicomponent protein nanomaterials to enable selective targeting and response to environment changes in a single unified framework. A novel protein nanoparticle platform has been designed to modulate cell-surface target specificity, cargo packaging, and pH-dependent release of encapsulated cargo, providing exciting possibilities in biologics delivery.
{"title":"Custom protein nanoparticles for targeted drug delivery","authors":"","doi":"10.1038/s41594-024-01289-4","DOIUrl":"10.1038/s41594-024-01289-4","url":null,"abstract":"Targeted biologics delivery requires programming multicomponent protein nanomaterials to enable selective targeting and response to environment changes in a single unified framework. A novel protein nanoparticle platform has been designed to modulate cell-surface target specificity, cargo packaging, and pH-dependent release of encapsulated cargo, providing exciting possibilities in biologics delivery.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 9","pages":"1317-1318"},"PeriodicalIF":12.5,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140895641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-08DOI: 10.1038/s41594-024-01302-w
Radhika Malik, Robert E. Johnson, Iban Ubarretxena-Belandia, Louise Prakash, Satya Prakash, Aneel K. Aggarwal
Rev1–Polζ-dependent translesion synthesis (TLS) of DNA is crucial for maintaining genome integrity. To elucidate the mechanism by which the two polymerases cooperate in TLS, we determined the cryogenic electron microscopic structure of the Saccharomyces cerevisiae Rev1–Polζ holocomplex in the act of DNA synthesis (3.53 Å). We discovered that a composite N-helix-BRCT module in Rev1 is the keystone of Rev1–Polζ cooperativity, interacting directly with the DNA template–primer and with the Rev3 catalytic subunit of Polζ. The module is positioned akin to the polymerase-associated domain in Y-family TLS polymerases and is set ideally to interact with PCNA. We delineate the full extent of interactions that the carboxy-terminal domain of Rev1 makes with Polζ and identify potential new druggable sites to suppress chemoresistance from first-line chemotherapeutics. Collectively, our results provide fundamental new insights into the mechanism of cooperativity between Rev1 and Polζ in TLS. The authors elucidate by cryo-EM the mechanism by which DNA polymerases Rev1 and Polζ cooperate in translesion DNA synthesis.
{"title":"Cryo-EM structure of the Rev1–Polζ holocomplex reveals the mechanism of their cooperativity in translesion DNA synthesis","authors":"Radhika Malik, Robert E. Johnson, Iban Ubarretxena-Belandia, Louise Prakash, Satya Prakash, Aneel K. Aggarwal","doi":"10.1038/s41594-024-01302-w","DOIUrl":"10.1038/s41594-024-01302-w","url":null,"abstract":"Rev1–Polζ-dependent translesion synthesis (TLS) of DNA is crucial for maintaining genome integrity. To elucidate the mechanism by which the two polymerases cooperate in TLS, we determined the cryogenic electron microscopic structure of the Saccharomyces cerevisiae Rev1–Polζ holocomplex in the act of DNA synthesis (3.53 Å). We discovered that a composite N-helix-BRCT module in Rev1 is the keystone of Rev1–Polζ cooperativity, interacting directly with the DNA template–primer and with the Rev3 catalytic subunit of Polζ. The module is positioned akin to the polymerase-associated domain in Y-family TLS polymerases and is set ideally to interact with PCNA. We delineate the full extent of interactions that the carboxy-terminal domain of Rev1 makes with Polζ and identify potential new druggable sites to suppress chemoresistance from first-line chemotherapeutics. Collectively, our results provide fundamental new insights into the mechanism of cooperativity between Rev1 and Polζ in TLS. The authors elucidate by cryo-EM the mechanism by which DNA polymerases Rev1 and Polζ cooperate in translesion DNA synthesis.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 9","pages":"1394-1403"},"PeriodicalIF":12.5,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140881287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-07DOI: 10.1038/s41594-024-01298-3
Daniel J. Sprague, Sang-Kyu Park, Svenja Gramberg, Lisa Bauer, Claudia M. Rohr, Evgeny G. Chulkov, Emery Smith, Louis Scampavia, Timothy P. Spicer, Simone Haeberlein, Jonathan S. Marchant
Diseases caused by parasitic flatworms impart a considerable healthcare burden worldwide. Many of these diseases—for example, the parasitic blood fluke infection schistosomiasis—are treated with the drug praziquantel (PZQ). However, PZQ is ineffective against disease caused by liver flukes from the genus Fasciola because of a single amino acid change within the target of PZQ, a transient receptor potential ion channel in the melastatin family (TRPMPZQ), in Fasciola species. Here, we identify benzamidoquinazolinone analogs that are active against Fasciola TRPMPZQ. Structure–activity studies define an optimized ligand (BZQ) that caused protracted paralysis and tegumental damage to these liver flukes. BZQ also retained activity against Schistosoma mansoni comparable to PZQ and was active against TRPMPZQ orthologs in all profiled species of parasitic fluke. This broad-spectrum activity manifests as BZQ adopts a pose within the binding pocket of TRPMPZQ that is dependent on a ubiquitously conserved residue. BZQ therefore acts as a universal activator of trematode TRPMPZQ and a first-in-class, broad-spectrum flukicide. The authors uncovered an antiparasitic molecule that exhibits broad-spectrum activity against parasitic flukes through engagement of a recently discovered transient receptor potential ion channel.
{"title":"Target-based discovery of a broad-spectrum flukicide","authors":"Daniel J. Sprague, Sang-Kyu Park, Svenja Gramberg, Lisa Bauer, Claudia M. Rohr, Evgeny G. Chulkov, Emery Smith, Louis Scampavia, Timothy P. Spicer, Simone Haeberlein, Jonathan S. Marchant","doi":"10.1038/s41594-024-01298-3","DOIUrl":"10.1038/s41594-024-01298-3","url":null,"abstract":"Diseases caused by parasitic flatworms impart a considerable healthcare burden worldwide. Many of these diseases—for example, the parasitic blood fluke infection schistosomiasis—are treated with the drug praziquantel (PZQ). However, PZQ is ineffective against disease caused by liver flukes from the genus Fasciola because of a single amino acid change within the target of PZQ, a transient receptor potential ion channel in the melastatin family (TRPMPZQ), in Fasciola species. Here, we identify benzamidoquinazolinone analogs that are active against Fasciola TRPMPZQ. Structure–activity studies define an optimized ligand (BZQ) that caused protracted paralysis and tegumental damage to these liver flukes. BZQ also retained activity against Schistosoma mansoni comparable to PZQ and was active against TRPMPZQ orthologs in all profiled species of parasitic fluke. This broad-spectrum activity manifests as BZQ adopts a pose within the binding pocket of TRPMPZQ that is dependent on a ubiquitously conserved residue. BZQ therefore acts as a universal activator of trematode TRPMPZQ and a first-in-class, broad-spectrum flukicide. The authors uncovered an antiparasitic molecule that exhibits broad-spectrum activity against parasitic flukes through engagement of a recently discovered transient receptor potential ion channel.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 9","pages":"1386-1393"},"PeriodicalIF":12.5,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140845337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-07DOI: 10.1038/s41594-024-01297-4
Klemens Rottner, Peter Bieling
Stabilization of a branch structure would intuitively suggest a direct connection between trunk and bough, but in actin filament networks, cortactin clamps the branching Arp2/3 complex to the daughter filament. This has fundamental consequences for mechanistic understanding of actin branch turnover and cortactin biology.
{"title":"Illuminating cortactin structure and function at actin filament branches","authors":"Klemens Rottner, Peter Bieling","doi":"10.1038/s41594-024-01297-4","DOIUrl":"10.1038/s41594-024-01297-4","url":null,"abstract":"Stabilization of a branch structure would intuitively suggest a direct connection between trunk and bough, but in actin filament networks, cortactin clamps the branching Arp2/3 complex to the daughter filament. This has fundamental consequences for mechanistic understanding of actin branch turnover and cortactin biology.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 5","pages":"739-741"},"PeriodicalIF":16.8,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140845261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-07DOI: 10.1038/s41594-024-01285-8
Ylli Doksani, Francisca Lottersberger
ADP-ribosylation regulates the activity of numerous proteins involved in the DNA damage response and repair. A new study shows that telomeric DNA can be ADP-ribosylated by PARP1, and prompt removal of the ADP-ribose by TARG1 is essential to preserve telomere integrity, unveiling DNA–ADP-ribosylation as a novel player in telomere stability.
{"title":"The risky business of ADP-ribosylating telomeric DNA","authors":"Ylli Doksani, Francisca Lottersberger","doi":"10.1038/s41594-024-01285-8","DOIUrl":"10.1038/s41594-024-01285-8","url":null,"abstract":"ADP-ribosylation regulates the activity of numerous proteins involved in the DNA damage response and repair. A new study shows that telomeric DNA can be ADP-ribosylated by PARP1, and prompt removal of the ADP-ribose by TARG1 is essential to preserve telomere integrity, unveiling DNA–ADP-ribosylation as a novel player in telomere stability.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 5","pages":"737-738"},"PeriodicalIF":16.8,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140845436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-07DOI: 10.1038/s41594-024-01279-6
Anne R. Wondisford, Junyeop Lee, Robert Lu, Marion Schuller, Josephine Groslambert, Ragini Bhargava, Sandra Schamus-Haynes, Leyneir C. Cespedes, Patricia L. Opresko, Hilda A. Pickett, Jaewon Min, Ivan Ahel, Roderick J. O’Sullivan
The recognition that DNA can be ADP ribosylated provides an unexpected regulatory level of how ADP-ribosylation contributes to genome stability, epigenetics and immunity. Yet, it remains unknown whether DNA ADP-ribosylation (DNA-ADPr) promotes genome stability and how it is regulated. Here, we show that telomeres are subject to DNA-ADPr catalyzed by PARP1 and removed by TARG1. Mechanistically, we show that DNA-ADPr is coupled to lagging telomere DNA strand synthesis, forming at single-stranded DNA present at unligated Okazaki fragments and on the 3′ single-stranded telomere overhang. Persistent DNA-linked ADPr, due to TARG1 deficiency, eventually leads to telomere shortening. Furthermore, using the bacterial DNA ADP-ribosyl-transferase toxin to modify DNA at telomeres directly, we demonstrate that unhydrolyzed DNA-linked ADP-ribose compromises telomere replication and telomere integrity. Thus, by identifying telomeres as chromosomal targets of PARP1 and TARG1-regulated DNA-ADPr, whose deregulation compromises telomere replication and integrity, our study highlights and establishes the critical importance of controlling DNA-ADPr turnover for sustained genome stability. Telomeres are endogenous cellular targets of DNA ADP-ribosylation (DNA-ADPr). TARG1-regulated DNA-ADPr is coupled to lagging telomere DNA strand synthesis, and persistent DNA-ADPr, due to TARG1 deficiency, leads to telomere shortening and fragility.
人们认识到 DNA 可以被 ADP 核糖基化，这为了解 ADP 核糖基化如何促进基因组稳定性、表观遗传学和免疫提供了一个意想不到的调控层面。然而，DNA ADP-核糖基化（DNA-ADPr）是否会促进基因组的稳定性以及它是如何被调控的仍是未知数。在这里，我们发现端粒会在 PARP1 的催化下发生 DNA-ADPr，并被 TARG1 清除。从机理上讲，我们发现DNA-ADPr与滞后端粒DNA链的合成相关联，在未连接的冈崎片段和3′单链端粒悬空处形成单链DNA。由于缺乏TARG1，DNA连接的ADPr持续存在，最终导致端粒缩短。此外，我们还利用细菌 DNA ADP-核糖基转移酶毒素直接修饰端粒的 DNA，证明未水解的 DNA 链接 ADP-ribose 会损害端粒复制和端粒完整性。因此，我们的研究通过确定端粒是 PARP1 和 TARG1 调节的 DNA-ADPr 的染色体靶标（其失调会损害端粒的复制和完整性），强调并确定了控制 DNA-ADPr 的周转对于持续的基因组稳定性至关重要。
{"title":"Deregulated DNA ADP-ribosylation impairs telomere replication","authors":"Anne R. Wondisford, Junyeop Lee, Robert Lu, Marion Schuller, Josephine Groslambert, Ragini Bhargava, Sandra Schamus-Haynes, Leyneir C. Cespedes, Patricia L. Opresko, Hilda A. Pickett, Jaewon Min, Ivan Ahel, Roderick J. O’Sullivan","doi":"10.1038/s41594-024-01279-6","DOIUrl":"10.1038/s41594-024-01279-6","url":null,"abstract":"The recognition that DNA can be ADP ribosylated provides an unexpected regulatory level of how ADP-ribosylation contributes to genome stability, epigenetics and immunity. Yet, it remains unknown whether DNA ADP-ribosylation (DNA-ADPr) promotes genome stability and how it is regulated. Here, we show that telomeres are subject to DNA-ADPr catalyzed by PARP1 and removed by TARG1. Mechanistically, we show that DNA-ADPr is coupled to lagging telomere DNA strand synthesis, forming at single-stranded DNA present at unligated Okazaki fragments and on the 3′ single-stranded telomere overhang. Persistent DNA-linked ADPr, due to TARG1 deficiency, eventually leads to telomere shortening. Furthermore, using the bacterial DNA ADP-ribosyl-transferase toxin to modify DNA at telomeres directly, we demonstrate that unhydrolyzed DNA-linked ADP-ribose compromises telomere replication and telomere integrity. Thus, by identifying telomeres as chromosomal targets of PARP1 and TARG1-regulated DNA-ADPr, whose deregulation compromises telomere replication and integrity, our study highlights and establishes the critical importance of controlling DNA-ADPr turnover for sustained genome stability. Telomeres are endogenous cellular targets of DNA ADP-ribosylation (DNA-ADPr). TARG1-regulated DNA-ADPr is coupled to lagging telomere DNA strand synthesis, and persistent DNA-ADPr, due to TARG1 deficiency, leads to telomere shortening and fragility.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 5","pages":"791-800"},"PeriodicalIF":16.8,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01279-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140845458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-03DOI: 10.1038/s41594-024-01277-8
Systemic RNA interference (RNAi) in Caenorhabditis elegans is initiated by SID-1-mediated double-stranded RNA (dsRNA) internalization. By combining cryo-electron microscopy (cryo-EM), in vitro and in vivo assays, we show how SID-1 specifically recognizes dsRNA and provide important insights into dsRNA internalization by SID-1.
{"title":"Cryo-EM structure reveals how SID-1 recognizes dsRNA that initiates systemic RNAi","authors":"","doi":"10.1038/s41594-024-01277-8","DOIUrl":"10.1038/s41594-024-01277-8","url":null,"abstract":"Systemic RNA interference (RNAi) in Caenorhabditis elegans is initiated by SID-1-mediated double-stranded RNA (dsRNA) internalization. By combining cryo-electron microscopy (cryo-EM), in vitro and in vivo assays, we show how SID-1 specifically recognizes dsRNA and provide important insights into dsRNA internalization by SID-1.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 7","pages":"1007-1008"},"PeriodicalIF":12.5,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140821231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-02DOI: 10.1038/s41594-024-01282-x
Uriel López-Sánchez, Lachlan Jake Munro, Lucy Kate Ladefoged, Anders Juel Pedersen, Christian Colding Brun, Signe Meisner Lyngby, Delphine Baud, Céline Juillan-Binard, Miriam Grønlund Pedersen, Sarah C. R. Lummis, Benny Bang-Andersen, Birgit Schiøtt, Christophe Chipot, Guy Schoehn, Jacques Neyton, Francois Dehez, Hugues Nury, Anders S. Kristensen
Vortioxetine (VTX) is a recently approved antidepressant that targets a variety of serotonin receptors. Here, we investigate the drug’s molecular mechanism of operation at the serotonin 5-HT3 receptor (5-HT3R), which features two properties: VTX acts differently on rodent and human 5-HT3R, and VTX appears to suppress any subsequent response to agonists. Using a combination of cryo-EM, electrophysiology, voltage-clamp fluorometry and molecular dynamics, we show that VTX stabilizes a resting inhibited state of the mouse 5-HT3R and an agonist-bound-like state of human 5-HT3R, in line with the functional profile of the drug. We report four human 5-HT3R structures and show that the human receptor transmembrane domain is intrinsically fragile. We also explain the lack of recovery after VTX administration via a membrane partition mechanism. The antidepressant vortioxetine affects rodent and human 5-HT3 receptors differently. López-Sánchez et al. use a variety of methods, including structure determination of vortioxetine-bound human and mouse 5-HT3 receptors, to reveal the basis of these differences.
{"title":"Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT3 receptors","authors":"Uriel López-Sánchez, Lachlan Jake Munro, Lucy Kate Ladefoged, Anders Juel Pedersen, Christian Colding Brun, Signe Meisner Lyngby, Delphine Baud, Céline Juillan-Binard, Miriam Grønlund Pedersen, Sarah C. R. Lummis, Benny Bang-Andersen, Birgit Schiøtt, Christophe Chipot, Guy Schoehn, Jacques Neyton, Francois Dehez, Hugues Nury, Anders S. Kristensen","doi":"10.1038/s41594-024-01282-x","DOIUrl":"10.1038/s41594-024-01282-x","url":null,"abstract":"Vortioxetine (VTX) is a recently approved antidepressant that targets a variety of serotonin receptors. Here, we investigate the drug’s molecular mechanism of operation at the serotonin 5-HT3 receptor (5-HT3R), which features two properties: VTX acts differently on rodent and human 5-HT3R, and VTX appears to suppress any subsequent response to agonists. Using a combination of cryo-EM, electrophysiology, voltage-clamp fluorometry and molecular dynamics, we show that VTX stabilizes a resting inhibited state of the mouse 5-HT3R and an agonist-bound-like state of human 5-HT3R, in line with the functional profile of the drug. We report four human 5-HT3R structures and show that the human receptor transmembrane domain is intrinsically fragile. We also explain the lack of recovery after VTX administration via a membrane partition mechanism. The antidepressant vortioxetine affects rodent and human 5-HT3 receptors differently. López-Sánchez et al. use a variety of methods, including structure determination of vortioxetine-bound human and mouse 5-HT3 receptors, to reveal the basis of these differences.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 8","pages":"1232-1242"},"PeriodicalIF":12.5,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140819487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-02DOI: 10.1038/s41594-024-01299-2
William R. Arnold, Adamo Mancino, Frank R. Moss III, Adam Frost, David Julius, Yifan Cheng
TRP ion channels are modulated by phosphoinositide lipids, but the underlying structural mechanisms remain unclear. The capsaicin- and heat-activated receptor, TRPV1, has served as a model for deciphering lipid modulation, which is relevant to understanding how pro-algesic agents enhance channel activity in the setting of inflammatory pain. Identification of a pocket within the TRPV1 transmembrane core has provided initial clues as to how phosphoinositide lipids bind to and regulate the channel. Here we show that this regulatory pocket in rat TRPV1 can accommodate diverse lipid species, including the inflammatory lipid lysophosphatidic acid, whose actions are determined by their specific modes of binding. Furthermore, we show that an empty-pocket channel lacking an endogenous phosphoinositide lipid assumes an agonist-like state, even at low temperature, substantiating the concept that phosphoinositide lipids serve as negative TRPV1 modulators whose ejection from the binding pocket is a critical step toward activation by thermal or chemical stimuli. Using cryo-EM, the authors elucidate the mechanisms of TRPV1 regulation by bioactive lipids, namely phosphoinositides and the inflammatory lipid lysophosphatidic acid.
{"title":"Structural basis of TRPV1 modulation by endogenous bioactive lipids","authors":"William R. Arnold, Adamo Mancino, Frank R. Moss III, Adam Frost, David Julius, Yifan Cheng","doi":"10.1038/s41594-024-01299-2","DOIUrl":"10.1038/s41594-024-01299-2","url":null,"abstract":"TRP ion channels are modulated by phosphoinositide lipids, but the underlying structural mechanisms remain unclear. The capsaicin- and heat-activated receptor, TRPV1, has served as a model for deciphering lipid modulation, which is relevant to understanding how pro-algesic agents enhance channel activity in the setting of inflammatory pain. Identification of a pocket within the TRPV1 transmembrane core has provided initial clues as to how phosphoinositide lipids bind to and regulate the channel. Here we show that this regulatory pocket in rat TRPV1 can accommodate diverse lipid species, including the inflammatory lipid lysophosphatidic acid, whose actions are determined by their specific modes of binding. Furthermore, we show that an empty-pocket channel lacking an endogenous phosphoinositide lipid assumes an agonist-like state, even at low temperature, substantiating the concept that phosphoinositide lipids serve as negative TRPV1 modulators whose ejection from the binding pocket is a critical step toward activation by thermal or chemical stimuli. Using cryo-EM, the authors elucidate the mechanisms of TRPV1 regulation by bioactive lipids, namely phosphoinositides and the inflammatory lipid lysophosphatidic acid.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 9","pages":"1377-1385"},"PeriodicalIF":12.5,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01299-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140819416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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