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


ABSTRACT: 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.

SUBMITTER: Lv Z 

PROVIDER: S-EPMC6279746 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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

Lv Zongyang Z   Yuan Lingmin L   Atkison James H JH   Williams Katelyn M KM   Vega Ramir R   Sessions E Hampton EH   Divlianska Daniela B DB   Davies Christopher C   Chen Yuan Y   Olsen Shaun K SK  

Nature communications 20181204 1


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 compl  ...[more]

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