Petzold Georg, Gainza Pablo, Annunziato Stefano, Lamberto Ilaria, Trenh Peter, McAllister Laura A, DeMarco Bradley, Schwander Laura, Bunker Richard D, Zlotosch Mary, SriRamaratnam Rohitha, Gilberto Samuel, Langousis Gerasimos, Donckele Etienne J, Quan Chao, Strande Vaik, De Donatis Gian Marco, Alabi Shanique B, Alers Jessica, Matysik Michelle, Staehly Camille, Dubois Aurélie, Osmont Arnaud, Garskovas Mackenzie, Lyon David, Wiedmer Lars, Oleinikovas Vladimiras, Lieberherr Raphael, Rubin Nooreen T, Lam Daniel T, Lucas Xavier, Liardo Elisa, Widlund Nina Ilic, Ritzén Andreas, Caceres Ramon Miguel, Vigil Dominico, Tsai Jennifer, Wallace Owen, Peluso Marisa, Sadok Amine, Tiedt Ralph, Paterson Alison M, Zarayskiy Vladislav, Fasching Bernhard, Bonenfant Debora, Warmuth Markus, Castle John C, Townson Sharon A
Monte Rosa Therapeutics Inc, Boston, MA, USA.
Science. 2025 Jul 3;389(6755):eadt6736. doi: 10.1126/science.adt6736.
The CRL4 E3 ubiquitin ligase is the target of molecular glue degrader compounds that reprogram ligase specificity to induce the degradation of clinically relevant neosubstrate proteins. Known cereblon (CRBN) neosubstrates share a generalizable β-hairpin G-loop recognition motif that allows for the systematic exploration of the CRBN target space. Computational mining approaches using structure- and surface-based matchmaking algorithms predict more than 1600 CRBN-compatible G-loop proteins across the human proteome, including the newly discovered helical G-loop motif, and identify the noncanonical neosubstrate binding mode of VAV1 that engages CRBN through a molecular surface mimicry mechanism. This work broadens the CRBN target space, redefines rules for neosubstrate recognition, and establishes a platform for the elimination of challenging drug targets by repurposing CRL4 through next-generation molecular glue degraders.
CRL4 E3泛素连接酶是分子胶降解剂化合物的作用靶点，这些化合物可重新编程连接酶特异性，以诱导临床相关新底物蛋白的降解。已知的大脑神经酰胺（CRBN）新底物具有一个可归纳的β-发夹G环识别基序，这使得对CRBN靶点空间进行系统探索成为可能。使用基于结构和表面的匹配算法的计算挖掘方法预测，整个人类蛋白质组中有超过1600种与CRBN兼容的G环蛋白，包括新发现的螺旋G环基序，并确定了通过分子表面模拟机制与CRBN结合的VAV1的非经典新底物结合模式。这项工作拓宽了CRBN靶点空间，重新定义了新底物识别规则，并通过下一代分子胶降解剂对CRL4进行重新利用，建立了一个消除具有挑战性的药物靶点的平台。
