6CWZ

Crystal structure of apo SUMO E1

Summary for 6CWZ

• Entry DOI: 10.2210/pdb6cwz/pdb
• Related: 6CWY
• Descriptor: SUMO-activating enzyme subunit 1, SUMO-activating enzyme subunit 2, ZINC ION (3 entities in total)
• Functional Keywords: rossmann-like fold, ubiquitin-like fold, ubiquitin activating enzyme, activity, atp binding, ligase activity, atp/mg binding, ubiquitin e2, ligase, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 112051.09

Authors

Lv, Z.,Yuan, L.,Atkison, J.H.,Williams, K.M.,Olsen, S.K. (deposition date: 2018-04-01, release date: 2019-01-16, Last modification date: 2023-10-04)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (3.1 Å)