Abstract
Post-translational modification of proteins by ubiquitin and ubiquitin-like proteins (collectively termed Ubls) proceeds through the sequential interactions and activities of parallel cascades of enzymes that are structurally and mechanistically related. E1 enzymes initiate Ub/Ubl conjugation cascades by catalyzing the ATP-dependent activation and transfer of their cognate Ub/Ubl to E2-conjugating enzymes, which then function with an array of E3 ligases to catalyze the formation of an isopeptide bond linking the Ub/Ubl to target proteins. Aberrations in Ub/Ubl modifications are associated with the pathogenesis of a wide range of life-threatening diseases, which has resulted in several Ubl E1 enzymes emerging as attractive targets for the development of small molecule therapeutics. We present the crystal structure of the E1 enzyme for the Ubl SUMO in complex with a small molecule representing a new class of Ubl E1 enzyme inhibitor. The structure reveals that the covalent allosteric inhibitor targets a cryptic pocket distinct from the active site that is completely buried in all previous SUMO E1 structures and that inhibitor binding is accompanied by a network of structural changes that altogether lock the enzyme in a previously unobserved inactive conformation. Altogether our studies provide the molecular mechanisms of inhibition SUMO E1 specificity and establishes a framework for the development of molecules targeting other Ubl E1s at a newly discovered cryptic allosteric site. Supported by NIH R01GM115568, F30CA216921, T32CA193201, and a Hollings Cancer Center Postdoctoral Fellowship. Citation Format: Zongyang Lyu, Lingmin Yuan, Katelyn M. Williams, James H. Atkison, Shaun K. Olsen. Molecular mechanism of a novel covalent allosteric inhibitor of SUMO E1 activating enzyme [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4435.
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