[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-detail-31901":3,"doc-seo-31901":27},{"code":4,"msg":5,"data":6},0,"success",{"doc_id":7,"user_id":8,"nickname":9,"user_avatar":10,"doc_module":4,"category_id":11,"category_name":12,"doc_title":13,"doc_description":14,"file_id":15,"file_url":16,"file_type":17,"file_size":18,"view_count":19,"is_deleted":4,"is_public":19,"is_downloadable":19,"audit_status":19,"page_count":20,"language":21,"language_code":22,"table_of_contents":23,"faqs":24,"seo_title":13,"seo_description":14,"update_tm":25,"read_time":26},31901,2336464648322,"Aria","https://ap-avatar.wpscdn.com/avatar/2200025388227c56fec?_k=1778556882303663488",8,"Research & Report","Druggability Is Not Static","Protein druggability is dynamically regulated rather than being an fixed property. Post-translational modifications (PTMs) reshape protein activity, structure, localization, and interaction networks, and a chemoproteomics approach maps how PTMs alter small-molecule–protein interactions across the proteome. Using photoaffinity probes and quantitative analysis under perturbations such as altered phosphorylation or N-linked glycosylation, the study identifies hundreds of PTM-dependent ligandability events. Results reveal local pocket effects and indirect PTM control at protein–protein interfaces, with clinical relevance demonstrated for KRAS inhibitor sensitivity.","cbCaivgS2tLAYFem","https://ap.wps.com/l/cbCaivgS2tLAYFem","pdf",961328,1,2,"English","en","# Protein PTMs and dynamic druggability\n## Proteome-wide chemoproteomic mapping\n## Modes of PTM-dependent regulation\n## Method overview and experimental strategy\n## Mechanistic insights and clinical implications","[{\"question\":\"How do post-translational modifications affect protein druggability?\",\"answer\":\"PTMs reshape the landscape of small-molecule–protein interactions, so ligandability changes with PTM state. The study shows hundreds of PTM-dependent binding events across the proteome.\"},{\"question\":\"What does the chemoproteomics workflow involve?\",\"answer\":\"The approach uses photoaffinity probes that crosslink to binding partners after UV activation, followed by enrichment and identification by mass spectrometry. Quantitative comparison between unperturbed and perturbed PTM states reveals ligandability shifts.\"},{\"question\":\"What are the two main mechanisms by which PTMs regulate ligandability?\",\"answer\":\"The work distinguishes direct local effects, where PTMs near pockets enable or hinder binding, from indirect effects, where distal PTMs remodel complexes to expose or occlude pockets at protein–protein interfaces.\"},{\"question\":\"How does PTM regulation relate to KRAS inhibitor sensitivity?\",\"answer\":\"KRAS switch-II pocket ligandability depends on phosphorylation at Tyr64, which weakens SOS1 binding and biases KRAS toward the inactive GDP-bound state. This inactive state corresponds to higher engagement by current KRAS G12C inhibitors such as sotorasib and adagrasib.\"}]",1780434098,5,{"code":4,"msg":28,"data":29},"ok",{"site_id":30,"language":22,"slug":31,"title":13,"keywords":32,"description":14,"schema_data":33,"social_meta":88,"head_meta":90,"extra_data":92,"updated_unix":25},105,"druggability-is-not-static","",{"@graph":34,"@context":87},[35,51,66],{"@type":36,"itemListElement":37},"BreadcrumbList",[38,42,45,48],{"item":39,"name":40,"@type":41,"position":19},"https://docshare.wps.com","Home","ListItem",{"item":43,"name":44,"@type":41,"position":20},"https://docshare.wps.com/document/","Document",{"item":46,"name":12,"@type":41,"position":47},"https://docshare.wps.com/document/research-report/",3,{"item":49,"name":13,"@type":41,"position":50},"https://docshare.wps.com/document/druggability-is-not-static/31901/",4,{"url":49,"name":13,"@type":52,"author":53,"headline":13,"publisher":55,"fileFormat":58,"description":14,"dateModified":59,"datePublished":60,"encodingFormat":58,"isAccessibleForFree":61,"interactionStatistic":62},"DigitalDocument",{"name":9,"@type":54},"Person",{"url":39,"name":56,"@type":57},"DocShare","Organization","application/pdf","2026-06-17","2026-06-02",true,{"@type":63,"interactionType":64,"userInteractionCount":19},"InteractionCounter",{"@type":65},"ViewAction",{"@type":67,"mainEntity":68},"FAQPage",[69,75,79,83],{"name":70,"@type":71,"acceptedAnswer":72},"How do post-translational modifications affect protein druggability?","Question",{"text":73,"@type":74},"PTMs reshape the landscape of small-molecule–protein interactions, so ligandability changes with PTM state. The study shows hundreds of PTM-dependent binding events across the proteome.","Answer",{"name":76,"@type":71,"acceptedAnswer":77},"What does the chemoproteomics workflow involve?",{"text":78,"@type":74},"The approach uses photoaffinity probes that crosslink to binding partners after UV activation, followed by enrichment and identification by mass spectrometry. Quantitative comparison between unperturbed and perturbed PTM states reveals ligandability shifts.",{"name":80,"@type":71,"acceptedAnswer":81},"What are the two main mechanisms by which PTMs regulate ligandability?",{"text":82,"@type":74},"The work distinguishes direct local effects, where PTMs near pockets enable or hinder binding, from indirect effects, where distal PTMs remodel complexes to expose or occlude pockets at protein–protein interfaces.",{"name":84,"@type":71,"acceptedAnswer":85},"How does PTM regulation relate to KRAS inhibitor sensitivity?",{"text":86,"@type":74},"KRAS switch-II pocket ligandability depends on phosphorylation at Tyr64, which weakens SOS1 binding and biases KRAS toward the inactive GDP-bound state. This inactive state corresponds to higher engagement by current KRAS G12C inhibitors such as sotorasib and adagrasib.","https://schema.org",{"og:url":49,"og:type":89,"og:title":13,"og:site_name":56,"og:description":14},"article",{"robots":91,"canonical":49},"index,follow",{"doc_id":7,"site_id":30}]