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

Publication Type:

Journal Article


Nat Commun, Volume 9, Issue 1, p.5145 (2018)


Allosteric Regulation, Catalytic Domain, Crystallography, X-Ray, Enzyme Activation, Enzyme Inhibitors, Humans, Models, Molecular, Protein Conformation, Protein Interaction Domains and Motifs, Ubiquitin, Ubiquitin-Activating Enzymes


<p>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&deg; 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.</p>