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/s41589-025-02079-9
Florent Figon
How biogenic crystals form within cells despite their building blocks being water insoluble is a conundrum. Now, it has been shown that zebrafish control the crystallization process by modulating organellar pH: first to accumulate guanine, and then to crystallize it.
{"title":"Acid enables biogenic crystallization","authors":"Florent Figon","doi":"10.1038/s41589-025-02079-9","DOIUrl":"10.1038/s41589-025-02079-9","url":null,"abstract":"How biogenic crystals form within cells despite their building blocks being water insoluble is a conundrum. Now, it has been shown that zebrafish control the crystallization process by modulating organellar pH: first to accumulate guanine, and then to crystallize it.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 1","pages":"7-8"},"PeriodicalIF":13.7,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145560175","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}
Pub Date : 2025-11-18DOI: 10.1038/s41589-025-02076-y
Zhi Lin, Wayne Ngo, Yu-Ting Chou, Harry Wu, Katherine J. Susa, Young-wook Jun, Trever G. Bivona, Jennifer A. Doudna, James A. Wells
Photoproximity labeling proteomics (PLP) methods have recently shown that cell surface receptors can form lateral interactome networks. Here, we present a paired set of PLP workflows that dynamically track neighborhood changes for oncogenic epidermal growth factor receptor (EGFR) over time, both outside and inside of cells. We achieved this by augmenting the multiscale PLP workflow we call MultiMap, where three photoprobes with different labeling ranges were photoactivated by one photocatalyst, eosin Y, anchored extracellularly and intracellularly on EGFR. We identified hundreds of neighboring proteins that changed within minutes to over 1 h after the addition of EGF. These neighborhoods reveal dynamic interactomes during early, middle and late signaling that drive phosphorylation, internalization, degradation and transcriptional regulation. This rapid ‘molecular photographic’ labeling approach provides snapshots of signaling neighborhoods, revealing their dynamic nature and potential for drug targeting. A multiscale photoproximity labeling proteomics workflow captures dynamic neighborhoods of extracellular and intracellular epidermal growth factor (EGF) receptor interactomes during early, middle and late signaling upon activation by EGF.
{"title":"Temporal photoproximity labeling of ligand-activated EGFR neighborhoods using MultiMap","authors":"Zhi Lin, Wayne Ngo, Yu-Ting Chou, Harry Wu, Katherine J. Susa, Young-wook Jun, Trever G. Bivona, Jennifer A. Doudna, James A. Wells","doi":"10.1038/s41589-025-02076-y","DOIUrl":"10.1038/s41589-025-02076-y","url":null,"abstract":"Photoproximity labeling proteomics (PLP) methods have recently shown that cell surface receptors can form lateral interactome networks. Here, we present a paired set of PLP workflows that dynamically track neighborhood changes for oncogenic epidermal growth factor receptor (EGFR) over time, both outside and inside of cells. We achieved this by augmenting the multiscale PLP workflow we call MultiMap, where three photoprobes with different labeling ranges were photoactivated by one photocatalyst, eosin Y, anchored extracellularly and intracellularly on EGFR. We identified hundreds of neighboring proteins that changed within minutes to over 1 h after the addition of EGF. These neighborhoods reveal dynamic interactomes during early, middle and late signaling that drive phosphorylation, internalization, degradation and transcriptional regulation. This rapid ‘molecular photographic’ labeling approach provides snapshots of signaling neighborhoods, revealing their dynamic nature and potential for drug targeting. A multiscale photoproximity labeling proteomics workflow captures dynamic neighborhoods of extracellular and intracellular epidermal growth factor (EGF) receptor interactomes during early, middle and late signaling upon activation by EGF.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 2","pages":"192-204"},"PeriodicalIF":13.7,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41589-025-02076-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145536138","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 : 2025-11-17DOI: 10.1038/s41589-025-02090-0
Russell Johnson
{"title":"A route to azetidine","authors":"Russell Johnson","doi":"10.1038/s41589-025-02090-0","DOIUrl":"10.1038/s41589-025-02090-0","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"21 12","pages":"1831-1831"},"PeriodicalIF":13.7,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531791","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 : 2025-11-17DOI: 10.1038/s41589-025-02088-8
Gene Chong
{"title":"Putting two and two together","authors":"Gene Chong","doi":"10.1038/s41589-025-02088-8","DOIUrl":"10.1038/s41589-025-02088-8","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"21 12","pages":"1831-1831"},"PeriodicalIF":13.7,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531793","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 : 2025-11-17DOI: 10.1038/s41589-025-02089-7
Yiyun Song
{"title":"It is the host Z-RNA at play","authors":"Yiyun Song","doi":"10.1038/s41589-025-02089-7","DOIUrl":"10.1038/s41589-025-02089-7","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"21 12","pages":"1831-1831"},"PeriodicalIF":13.7,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531792","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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