Pub Date : 2025-12-05DOI: 10.1038/s41589-025-02083-z
Karla M. Castro, Joseph L. Watson, Jue Wang, Joshua Southern, Reyhaneh Ayardulabi, Sandrine Georgeon, Stéphane Rosset, David Baker, Bruno E. Correia
De novo protein design has seen major success in scaffolding single functional motifs; however, in nature, most proteins present multiple functional sites. Here, we describe an approach to simultaneously scaffold multiple functional sites in a single-domain protein using deep learning. We designed small single-domain immunogens, under 130 residues, that present three distinct and irregular motifs from respiratory syncytial virus. These motifs together comprise nearly half of the designed proteins; hence, the overall folds are quite unusual with little global similarity to proteins in the Protein Data Bank. Despite this, X-ray crystal structures confirmed the accuracy of presentation of each of the motifs and the multiepitope design yields improved cross-reactive titers and neutralizing response compared to a single-epitope immunogen. The successful presentation of three distinct binding surfaces in a small single-domain protein highlights the power of generative deep learning methods to solve complex protein design problems.
{"title":"Accurate single-domain scaffolding of three nonoverlapping protein epitopes using deep learning","authors":"Karla M. Castro, Joseph L. Watson, Jue Wang, Joshua Southern, Reyhaneh Ayardulabi, Sandrine Georgeon, Stéphane Rosset, David Baker, Bruno E. Correia","doi":"10.1038/s41589-025-02083-z","DOIUrl":"https://doi.org/10.1038/s41589-025-02083-z","url":null,"abstract":"De novo protein design has seen major success in scaffolding single functional motifs; however, in nature, most proteins present multiple functional sites. Here, we describe an approach to simultaneously scaffold multiple functional sites in a single-domain protein using deep learning. We designed small single-domain immunogens, under 130 residues, that present three distinct and irregular motifs from respiratory syncytial virus. These motifs together comprise nearly half of the designed proteins; hence, the overall folds are quite unusual with little global similarity to proteins in the Protein Data Bank. Despite this, X-ray crystal structures confirmed the accuracy of presentation of each of the motifs and the multiepitope design yields improved cross-reactive titers and neutralizing response compared to a single-epitope immunogen. The successful presentation of three distinct binding surfaces in a small single-domain protein highlights the power of generative deep learning methods to solve complex protein design problems.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"15 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145680727","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 : 2025-12-01DOI: 10.1038/s41589-025-02078-w
{"title":"Configurational isomerization around the metal center underlies chemoselectivity of a radical halogenase","authors":"","doi":"10.1038/s41589-025-02078-w","DOIUrl":"https://doi.org/10.1038/s41589-025-02078-w","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"21 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145645239","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 : 2025-11-27DOI: 10.1038/s41589-025-02080-2
Anfei Huang, Wolfgang Kastenmüller
{"title":"Mapping cellular contacts in situ","authors":"Anfei Huang, Wolfgang Kastenmüller","doi":"10.1038/s41589-025-02080-2","DOIUrl":"https://doi.org/10.1038/s41589-025-02080-2","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"10 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145609442","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 : 2025-11-21DOI: 10.1038/s41589-025-02075-z
Benzhen Duan, Xiaohui Jin, Xiaoman An, Yang Xiao, Qianxi Yang, Hongyu Zhao, Yunxiao Huang, Jingwen Wang, Qian Wang, Fenglei Du, Lu Lu, Lei Sun, Zhenguo Chen, Baoyu Zhao
{"title":"Molecular basis of SAM-AMP synthesis and degradation in the type III-B CRISPR–Cas system","authors":"Benzhen Duan, Xiaohui Jin, Xiaoman An, Yang Xiao, Qianxi Yang, Hongyu Zhao, Yunxiao Huang, Jingwen Wang, Qian Wang, Fenglei Du, Lu Lu, Lei Sun, Zhenguo Chen, Baoyu Zhao","doi":"10.1038/s41589-025-02075-z","DOIUrl":"https://doi.org/10.1038/s41589-025-02075-z","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"35 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145560360","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 : 2025-11-21DOI: 10.1038/s41589-025-02077-x
Elijah N. Kissman, Ioannis Kipouros, Jeffrey W. Slater, Elizabeth A. Stone, Avery Y. Yang, Augustin Braun, Alder R. Ensberg, Andrew M. Whitten, Kuntal Chatterjee, Isabel Bogacz, Junko Yano, J. Martin Bollinger, Michelle C. Y. Chang
{"title":"Dynamic metal coordination controls chemoselectivity in a radical halogenase","authors":"Elijah N. Kissman, Ioannis Kipouros, Jeffrey W. Slater, Elizabeth A. Stone, Avery Y. Yang, Augustin Braun, Alder R. Ensberg, Andrew M. Whitten, Kuntal Chatterjee, Isabel Bogacz, Junko Yano, J. Martin Bollinger, Michelle C. Y. Chang","doi":"10.1038/s41589-025-02077-x","DOIUrl":"https://doi.org/10.1038/s41589-025-02077-x","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"170 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145560362","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 : 2025-11-21DOI: 10.1038/s41589-025-02058-0
Casey E. Wing, Ho Yee Joyce Fung, Bert Kwanten, Tolga Cagatay, Ashley B. Niesman, Maarten Jacquemyn, Mehdi Gharghabi, Brecht Permentier, Binita Shakya, Rhituparna Nandi, Joseph M. Ready, Trinayan Kashyap, Sharon Shacham, Yosef Landesman, Rosa Lapalombella, Dirk Daelemans, Yuh Min Chook
Overexpression of exportin 1 (XPO1/CRM1) in cancer cells mislocalizes numerous cancer-related nuclear export cargoes. Covalent selective inhibitors of nuclear export (SINEs), including the cancer drug selinexor, restore proper nuclear localization by blocking XPO1–cargo interaction. These inhibitors also induce XPO1 degradation through the Cullin–RING E3 ligase (CRL) substrate receptor ASB8. Here we present cryo-electron microscopy structures revealing ASB8 binding to a cryptic XPO1 site that is exposed upon SINE conjugation. Unlike typical molecular glue degraders that directly bridge CRLs and substrates, SINEs bind XPO1 independently of ASB8, triggering an allosteric mechanism that enables high-affinity ASB8 recruitment, leading to XPO1 ubiquitination and degradation. ASB8-mediated degradation is also triggered by the endogenous itaconate derivative 4-octyl itaconate, suggesting that synthetic XPO1 inhibitors exploit a native cellular mechanism. This allosteric XPO1 degradation mechanism expands known modes of targeted protein degradation beyond molecular glue degraders and proteolysis-targeting chimeras of CRL4. Selinexor is a covalent inhibitor of the nuclear export receptor exportin 1 (XPO1). Wing, Fung and Kwanten et al. found that selinexor mediates XPO1 degradation through an allosteric molecule glue mechanism, stabilizing XPO1 in a conformation capable of binding to the E3 Cullin–RING E3 ligase 5 substrate receptor ASB8.
{"title":"SINE compounds activate exportin 1 degradation through an allosteric mechanism","authors":"Casey E. Wing, Ho Yee Joyce Fung, Bert Kwanten, Tolga Cagatay, Ashley B. Niesman, Maarten Jacquemyn, Mehdi Gharghabi, Brecht Permentier, Binita Shakya, Rhituparna Nandi, Joseph M. Ready, Trinayan Kashyap, Sharon Shacham, Yosef Landesman, Rosa Lapalombella, Dirk Daelemans, Yuh Min Chook","doi":"10.1038/s41589-025-02058-0","DOIUrl":"10.1038/s41589-025-02058-0","url":null,"abstract":"Overexpression of exportin 1 (XPO1/CRM1) in cancer cells mislocalizes numerous cancer-related nuclear export cargoes. Covalent selective inhibitors of nuclear export (SINEs), including the cancer drug selinexor, restore proper nuclear localization by blocking XPO1–cargo interaction. These inhibitors also induce XPO1 degradation through the Cullin–RING E3 ligase (CRL) substrate receptor ASB8. Here we present cryo-electron microscopy structures revealing ASB8 binding to a cryptic XPO1 site that is exposed upon SINE conjugation. Unlike typical molecular glue degraders that directly bridge CRLs and substrates, SINEs bind XPO1 independently of ASB8, triggering an allosteric mechanism that enables high-affinity ASB8 recruitment, leading to XPO1 ubiquitination and degradation. ASB8-mediated degradation is also triggered by the endogenous itaconate derivative 4-octyl itaconate, suggesting that synthetic XPO1 inhibitors exploit a native cellular mechanism. This allosteric XPO1 degradation mechanism expands known modes of targeted protein degradation beyond molecular glue degraders and proteolysis-targeting chimeras of CRL4. Selinexor is a covalent inhibitor of the nuclear export receptor exportin 1 (XPO1). Wing, Fung and Kwanten et al. found that selinexor mediates XPO1 degradation through an allosteric molecule glue mechanism, stabilizing XPO1 in a conformation capable of binding to the E3 Cullin–RING E3 ligase 5 substrate receptor ASB8.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"21 12","pages":"2002-2013"},"PeriodicalIF":13.7,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145560179","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 : 2025-11-21DOI: 10.1038/s41589-025-02059-z
Laura A. Schneider, Alexandra M. Bendel, Regina Baur, Nicolas H. Thomä
Molecular glue degraders induce or stabilize interactions between E3 ligases and target proteins. Beyond compound-induced, direct interactions, researchers recently uncovered an allosteric mechanism whereby a drug alters the target protein’s conformation, enabling high-affinity neo-binding to an E3 ligase and triggering degradation.
{"title":"Gluing the allosteric way","authors":"Laura A. Schneider, Alexandra M. Bendel, Regina Baur, Nicolas H. Thomä","doi":"10.1038/s41589-025-02059-z","DOIUrl":"10.1038/s41589-025-02059-z","url":null,"abstract":"Molecular glue degraders induce or stabilize interactions between E3 ligases and target proteins. Beyond compound-induced, direct interactions, researchers recently uncovered an allosteric mechanism whereby a drug alters the target protein’s conformation, enabling high-affinity neo-binding to an E3 ligase and triggering degradation.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"21 12","pages":"1835-1836"},"PeriodicalIF":13.7,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145560359","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}
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