Snapshots and ensembles of BTK and cIAP1 protein degrader ternary complexes

被引：62

作者：

Schiemer, James ^{[1
]}

Horst, Reto ^{[1
]}

Meng, Yilin ^{[1
]}

Montgomery, Justin I. ^{[1
]}

Xu, Yingrong ^{[1
]}

Feng, Xidong ^{[1
]}

Borzilleri, Kris ^{[1
]}

Uccello, Daniel P. ^{[1
]}

Leverett, Carolyn ^{[1
]}

Brown, Stephen ^{[1
]}

Che, Ye ^{[1
]}

Brown, Matthew F. ^{[1
]}

Hayward, Matthew M. ^{[1
]}

Gilbert, Adam M. ^{[1
]}

Noe, Mark C. ^{[1
]}

Calabrese, Matthew F. ^{[1
]}

机构：

[1] Pfizer Worldwide Res & Dev, Discovery Sci, Groton, CT 06340 USA

来源：

NATURE CHEMICAL BIOLOGY | 2021年 / 17卷 / 02期

关键词：

SMALL-MOLECULE INHIBITORS; DEGRADATION INDUCER; ANTAGONISTS INDUCE; KINASE INHIBITORS; SMAC MIMETICS; TARGETING BTK; KNOCKDOWN; POTENT; ACTIVATION; DISCOVERY;

D O I：

10.1038/s41589-020-00686-2

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Heterobifunctional chimeric degraders are a class of ligands that recruit target proteins to E3 ubiquitin ligases to drive compound-dependent protein degradation. Advancing from initial chemical tools, protein degraders represent a mechanism of growing interest in drug discovery. Critical to the mechanism of action is the formation of a ternary complex between the target, degrader and E3 ligase to promote ubiquitination and subsequent degradation. However, limited insights into ternary complex structures exist, including a near absence of studies on one of the most widely co-opted E3s, cellular inhibitor of apoptosis 1 (cIAP1). In this work, we use a combination of biochemical, biophysical and structural studies to characterize degrader-mediated ternary complexes of Bruton's tyrosine kinase and cIAP1. Our results reveal new insights from unique ternary complex structures and show that increased ternary complex stability or rigidity need not always correlate with increased degradation efficiency.

引用

页码：152 / 160

页数：9