Structural Basis and Kinetic Pathway of RBM39 Recruitment to DCAF15 by a Sulfonamide Molecular Glue E7820

被引：126

作者：

Du, Xinlin ^{[1
,2
]}

Volkov, Oleg A. ^{[1
,2
]}

Czerwinski, Robert M. ^{[1
,2
]}

Tan, HuiLing ^{[1
,2
]}

Huerta, Carlos ^{[1
,2
]}

Morton, Emily R. ^{[1
,2
]}

Rizzi, Jim P. ^{[1
,2
]}

Wehn, Paul M. ^{[1
,2
]}

Xu, Rui ^{[1
,2
]}

Nijhawan, Deepak ^{[3
,4
]}

Wallace, Eli M. ^{[1
,2
]}

机构：

[1] Peloton Therapeut, Dallas, TX 75235 USA

[2] Merck & Co Inc, Kenilworth, NJ 07033 USA

[3] Univ Texas Southwestern Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA

[4] Univ Texas Southwestern Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA

来源：

STRUCTURE | 2019年 / 27卷 / 11期

关键词：

UBIQUITIN LIGASE; SELECTIVE DEGRADATION; INTEGRIN ALPHA-2; PROTEIN; ARCHITECTURE; INHIBITOR; MODEL; COMPLEX; REFMAC5; PHASE;

D O I：

10.1016/j.str.2019.10.005

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：

E7820 and indisulam are two examples of aryl sulfonamides that recruit RBM39 to Rbx-Cul4-DDA1DDB1-DCAF15 E3 ligase complex, leading to its ubiquitination and degradation by the proteasome. To understand their mechanism of action, we performed kinetic analysis on the recruitment of RBM39 to DCAF15 and solved a crystal structure of DDA1-DDB1-DCAF15 in complex with E7820 and the RRM2 domain of RBM39. E7820 packs in a shallow pocket on the surface of DCAF15 and the resulting modified interface binds RBM39 through the alpha 1 helix of the RRM2 domain. Our kinetic studies revealed that aryl sulfonamide and RBM39 bind to DCAF15 in a synergistic manner. The structural and kinetic studies confirm aryl sulfonamides as molecular glues in the recruitment of RBM39 and provide a framework for future efforts to utilize DCAF15 to degrade other proteins of interest.

引用

页码：1625 / +

页数：12

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