{"id":2219,"date":"2020-11-11T14:58:00","date_gmt":"2020-11-11T14:58:00","guid":{"rendered":"https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/?p=2219"},"modified":"2026-01-26T16:28:03","modified_gmt":"2026-01-26T16:28:03","slug":"building-and-hijacking-ubiquitination-machineries-by-protacs","status":"publish","type":"post","link":"https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/2020\/11\/11\/building-and-hijacking-ubiquitination-machineries-by-protacs\/","title":{"rendered":"Building and hijacking ubiquitination machineries by PROTACs"},"content":{"rendered":"<p>Our review on building and hijacking ubiquitination machineries by PROTACs and glues is now out in Current Opinion in Structural Biology<\/p>\n<p>Congratulations to Sarath on this review article. We hope people will find it useful!<\/p>\n<p><a href=\"https:\/\/doi.org\/10.1016\/j.sbi.2020.10.009\">Read the Open Access full article<\/a>.<\/p>\n<p><strong>Authors<\/strong>: Sarath Ramachandran and Alessio Ciulli*<\/p>\n<p><strong>Title<\/strong>: Building ubiquitination machineries: E3 ligase multi-subunit assembly and substrate targeting by PROTACs and molecular glues<\/p>\n<p><strong>Highlights:<\/strong><\/p>\n<ul>\n<li>E3 ligase machineries confer specificity to protein ubiquitination.<\/li>\n<li>Multi-subunit assembly and substrate recognition impact E3 ligase activity.<\/li>\n<li>Molecular glues and PROTACs recruit proteins to E3 ligases for targeted degradation.<\/li>\n<li>E3: PROTAC\/glue: target ternary complex structures can accelerate degrader design.<\/li>\n<\/ul>\n<h2 class=\"wp-block-heading\"><strong>Abstract<\/strong><\/h2>\n<p>E3 ubiquitin ligase machineries are emerging as attractive therapeutic targets because they confer specificity to substrate ubiquitination and can be hijacked for targeted protein degradation. In this review, we bring to focus our current structural understanding of E3 ligase complexes, in particular the multi-subunit cullin RING ligases, and modulation thereof by small-molecule glues and PROTAC degraders. We highlight recent advances in elucidating the modular assembly of E3 ligase machineries, their diverse substrate and degron recognition mechanisms, and how these structural features impact on ligase function. We then outline the emergence of structures of E3 ligases bound to neo-substrates and degrader molecules, and highlight the importance of studying such ternary complexes for structure-based degrader design.<\/p>\n<div id='gallery-1' class='gallery galleryid-2219 gallery-columns-3 gallery-size-large'><figure class='gallery-item'>\n\t\t\t<div class='gallery-icon landscape'>\n\t\t\t\t<a href='https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-1.jpg'><img loading=\"lazy\" decoding=\"async\" width=\"1024\" height=\"401\" src=\"https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-1-1024x401.jpg\" class=\"attachment-large size-large\" alt=\"Graphic abstract of Building E3 Ligase ubiquitination\" srcset=\"https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-1-1024x401.jpg 1024w, https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-1-300x117.jpg 300w, https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-1-768x301.jpg 768w, https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-1.jpg 1333w\" sizes=\"auto, (max-width: 1024px) 100vw, 1024px\" \/><\/a>\n\t\t\t<\/div><\/figure><figure class='gallery-item'>\n\t\t\t<div class='gallery-icon landscape'>\n\t\t\t\t<a href='https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-2.jpg'><img loading=\"lazy\" decoding=\"async\" width=\"1024\" height=\"681\" src=\"https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-2-1024x681.jpg\" class=\"attachment-large size-large\" alt=\"Figure 1. Structural assembly of modular multi-subunit E3 ligases\" srcset=\"https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-2-1024x681.jpg 1024w, https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-2-300x200.jpg 300w, https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-2-768x511.jpg 768w, https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-2-1536x1022.jpg 1536w, https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-2-2048x1362.jpg 2048w\" sizes=\"auto, (max-width: 1024px) 100vw, 1024px\" \/><\/a>\n\t\t\t<\/div><\/figure><figure class='gallery-item'>\n\t\t\t<div class='gallery-icon landscape'>\n\t\t\t\t<a href='https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-3.jpg'><img loading=\"lazy\" decoding=\"async\" width=\"1024\" height=\"595\" src=\"https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-3-1024x595.jpg\" class=\"attachment-large size-large\" alt=\"Figure 2. Substrate recognition by E3 ligase substrate receptors\" srcset=\"https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-3-1024x595.jpg 1024w, https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-3-300x174.jpg 300w, https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-3-768x446.jpg 768w, https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-3-1536x893.jpg 1536w, https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-3-2048x1190.jpg 2048w\" sizes=\"auto, (max-width: 1024px) 100vw, 1024px\" \/><\/a>\n\t\t\t<\/div><\/figure><figure class='gallery-item'>\n\t\t\t<div class='gallery-icon landscape'>\n\t\t\t\t<a href='https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-4.jpg'><img loading=\"lazy\" decoding=\"async\" width=\"1024\" height=\"639\" src=\"https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-4-1024x639.jpg\" class=\"attachment-large size-large\" alt=\"Figure 3. Ternary complexes of E3 ligases with molecular glue degraders\" srcset=\"https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-4-1024x639.jpg 1024w, https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-4-300x187.jpg 300w, https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-4-768x479.jpg 768w, https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-4-1536x958.jpg 1536w, https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-4-2048x1278.jpg 2048w\" sizes=\"auto, (max-width: 1024px) 100vw, 1024px\" \/><\/a>\n\t\t\t<\/div><\/figure><figure class='gallery-item'>\n\t\t\t<div class='gallery-icon landscape'>\n\t\t\t\t<a href='https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-5.jpg'><img loading=\"lazy\" decoding=\"async\" width=\"1024\" height=\"778\" src=\"https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-5-1024x778.jpg\" class=\"attachment-large size-large\" alt=\"Figure 4. Crystal structures of E3 ligase-PROTAC-Target protein ternary complexes\" srcset=\"https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-5-1024x778.jpg 1024w, https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-5-300x228.jpg 300w, https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-5-768x583.jpg 768w, https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-5-1536x1167.jpg 1536w, https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-content\/uploads\/sites\/233\/2024\/01\/Building-ubiquitination-machineries-E3-ligase-5-2048x1556.jpg 2048w\" sizes=\"auto, (max-width: 1024px) 100vw, 1024px\" \/><\/a>\n\t\t\t<\/div><\/figure>\n\t\t<\/div>\n\n","protected":false},"excerpt":{"rendered":"<p>Our review on building and hijacking ubiquitination machineries by PROTACs and glues is now out in Current Opinion in Structural Biology Congratulations to Sarath on this review article. We hope people will find it useful! Read the Open Access full article. Authors: Sarath Ramachandran and Alessio Ciulli* Title: Building ubiquitination machineries: E3 ligase multi-subunit assembly [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[15,4],"tags":[],"class_list":["post-2219","post","type-post","status-publish","format-standard","hentry","category-15","category-news"],"blocksy_meta":[],"_links":{"self":[{"href":"https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-json\/wp\/v2\/posts\/2219","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-json\/wp\/v2\/comments?post=2219"}],"version-history":[{"count":2,"href":"https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-json\/wp\/v2\/posts\/2219\/revisions"}],"predecessor-version":[{"id":4848,"href":"https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-json\/wp\/v2\/posts\/2219\/revisions\/4848"}],"wp:attachment":[{"href":"https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-json\/wp\/v2\/media?parent=2219"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-json\/wp\/v2\/categories?post=2219"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/wp-json\/wp\/v2\/tags?post=2219"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}