6CWY

Crystal structure of SUMO E1 in complex with an allosteric inhibitor

6CWY の概要

• エントリーDOI: 10.2210/pdb6cwy/pdb
• 分子名称: SUMO-activating enzyme subunit 1, SUMO-activating enzyme subunit 2, GLYCEROL, ... (8 entities in total)
• 機能のキーワード: rossmann-like fold, ubiquitin-like fold, ubiquitin activating enzyme, activity, atp binding, ligase activity, atp/mg binding, ubiquitin e2, ligase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 113065.32

構造登録者

Lv, Z.,Yuan, L.,Atkison, J.H.,Williams, K.M.,Olsen, S.K. (登録日: 2018-04-01, 公開日: 2019-01-16, 最終更新日: 2024-10-23)

主引用文献

Lv, Z.,Yuan, L.,Atkison, J.H.,Williams, K.M.,Vega, R.,Sessions, E.H.,Divlianska, D.B.,Davies, C.,Chen, Y.,Olsen, S.K.
Molecular mechanism of a covalent allosteric inhibitor of SUMO E1 activating enzyme.
Nat Commun, 9:5145-5145, 2018

PubMed 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.

PubMed: 30514846
DOI: 10.1038/s41467-018-07015-1

実験手法

X-RAY DIFFRACTION (2.462 Å)