Molecular mechanism of a covalent allosteric inhibitor of SUMO E1 activating enzyme.

Autor:	Lv Z; Department of Biochemistry & Molecular Biology and Hollings Cancer Center, Medical University of South Carolina, Charleston, 29425, SC, USA., Yuan L; Department of Biochemistry & Molecular Biology and Hollings Cancer Center, Medical University of South Carolina, Charleston, 29425, SC, USA., Atkison JH; Department of Biochemistry & Molecular Biology and Hollings Cancer Center, Medical University of South Carolina, Charleston, 29425, SC, USA., Williams KM; Department of Biochemistry & Molecular Biology and Hollings Cancer Center, Medical University of South Carolina, Charleston, 29425, SC, USA., Vega R; Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, 91010, CA, USA., Sessions EH; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, 32827, FL, USA., Divlianska DB; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, 32827, FL, USA., Davies C; Department of Biochemistry & Molecular Biology and Hollings Cancer Center, Medical University of South Carolina, Charleston, 29425, SC, USA., Chen Y; Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, 91010, CA, USA. ychen@coh.org., Olsen SK; Department of Biochemistry & Molecular Biology and Hollings Cancer Center, Medical University of South Carolina, Charleston, 29425, SC, USA. olsensk@musc.edu.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2018 Dec 04; Vol. 9 (1), pp. 5145. Date of Electronic Publication: 2018 Dec 04.
DOI:	10.1038/s41467-018-07015-1
Abstrakt:	E1 enzymes activate ubiquitin (Ub) and ubiquitin-like modifiers (Ubls) in the first step of Ub/Ubl conjugation cascades and represent potential targets for therapeutic intervention in cancer and other life-threatening diseases. Here, we report the crystal structure of the E1 enzyme for the Ubl SUMO in complex with a recently discovered and highly specific covalent allosteric inhibitor (COH000). The structure reveals that COH000 targets a cryptic pocket distinct from the active site that is completely buried in all previous SUMO E1 structures and that COH000 binding to SUMO E1 is accompanied by a network of structural changes that altogether lock the enzyme in a previously unobserved inactive conformation. These structural changes include disassembly of the active site and a 180° rotation of the catalytic cysteine-containing SCCH domain, relative to conformational snapshots of SUMO E1 poised to catalyze adenylation. Altogether, our study provides a molecular basis for the inhibitory mechanism of COH000 and its SUMO E1 specificity, and also establishes a framework for potential development of molecules targeting E1 enzymes for other Ubls at a cryptic allosteric site.
Databáze:	MEDLINE
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