Journal Article

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

Divlianska, Daniela B., Atkison, James H., Williams, Katelyn M., Lv, Zongyang, Chen, Yuan, Vega, Ramir, Yuan, Lingmin, Sessions, E. Hampton, Davies, Christopher, Olsen, Shaun K.

2018

Overview

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. Ubiquitin and ubiquitin-like modifiers such as SUMO play important roles in several cellular pathways that can become deregulated in cancer. Here the authors describe the structural basis for inhibition of SUMO E1 ligase by the small molecule COH000.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/45/173 / 631/45/474/2288 / 631/45/474/538 / 631/45/474/582 / 631/535/1266 / Adenylation / Allosteric properties / Allosteric Regulation / BASIC BIOLOGICAL SCIENCES / Buried structures / Cancer / Cascades / Catalysis / Catalytic Domain / Conformation / Conjugation / Crystal structure / Crystallography, X-Ray / Dismantling / Enzyme Activation / Enzyme Inhibitors - chemistry / Enzyme Inhibitors - pharmacology / Enzyme mechanisms / Enzymes / Humanities and Social Sciences / Humans / Inhibitors / Models, Molecular / multidisciplinary / Neddylation / Protein Conformation / Protein Interaction Domains and Motifs / Science / Science (multidisciplinary) / Sumoylation / Ubiquitin / Ubiquitin - chemistry / Ubiquitin - metabolism / Ubiquitin-Activating Enzymes - antagonists & inhibitors / Ubiquitin-Activating Enzymes - chemistry / Ubiquitin-Activating Enzymes - genetics / Ubiquitin-Activating Enzymes - metabolism / Ubiquitylation / X-ray crystallography