Insights Into the Allosteric Inhibition of the SUMO E2 Enzyme Ubc9

Hewitt, William M.; Lountos, George T.; Zlotkowski, Katherine; Dahlhauser, Samuel D.; Saunders, Lindsey B.; Needle, Danielle; Tropea, Joseph E.; Zhan, Chendi; Wei, Guanghong; Ma, Buyong; Nussinov, Ruth; Waugh, David S.; Schneekloth, Jr., John S.

doi:10.1002/anie.201511351

Title: Insights Into the Allosteric Inhibition of the SUMO E2 Enzyme Ubc9

Journal Article · Fri Apr 01 00:00:00 EDT 2016 · Angewandte Chemie (International Edition)

DOI:https://doi.org/10.1002/anie.201511351· OSTI ID:1249263

Hewitt, William M. ^[1]; Lountos, George T. ^[2]; Zlotkowski, Katherine ^[1]; Dahlhauser, Samuel D. ^[1]; Saunders, Lindsey B. ^[1]; Needle, Danielle ^[1]; Tropea, Joseph E. ^[1]; Zhan, Chendi ^[3];

^[3];

^[4]; Nussinov, Ruth ^[5];

^[1];

^[1]

National Cancer Inst. (NCI), Frederick, MD (United States)
National Cancer Inst. (NCI), Frederick, MD (United States); Leidos Biomedical Research, Inc., Frederick, MD (United States). Frederick National Lab. for Cancer Research
Fudan Univ., Shanghai (China)
Leidos Biomedical Research, Inc. Frederick, MD (United States); National Cancer Inst. (NCI), Frederick MD (United States)
Leidos Biomedical Research, Inc. Frederick, MD (United States); National Cancer Inst. (NCI), Frederick MD (United States); Tel Aviv Univ. (Israel)

Conjugation of the small ubiquitin-like modifier (SUMO) to protein substrates is an important disease-associated posttranslational modification, although few inhibitors of this process are known. In this paper, we report the discovery of an allosteric small-molecule binding site on Ubc9, the sole SUMO E2 enzyme. An X-ray crystallographic screen was used to identify two distinct small-molecule fragments that bind to Ubc9 at a site distal to its catalytic cysteine. These fragments and related compounds inhibit SUMO conjugation in biochemical assays with potencies of 1.9–5.8 mm. Mechanistic and biophysical analyses, coupled with molecular dynamics simulations, point toward ligand-induced rigidification of Ubc9 as a mechanism of inhibition.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); National Cancer Institute (NCI); USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: HHSN261200800001E; W-31-109-Eng-38

OSTI ID:: 1249263

Journal Information:: Angewandte Chemie (International Edition), Vol. 55, Issue 19; ISSN 1433-7851

Publisher:: WileyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 15 works

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Allosteric mechanism for site-specific ubiquitination of FANCD2 Chaugule, Viduth K.; Arkinson, Connor; Rennie, Martin L. Nature Chemical Biology, Vol. 16, Issue 3 https://doi.org/10.1038/s41589-019-0426-z	journal	December 2019
Expression of SUMO associated proteins in the mouse endometrium is regulated by ovarian hormones throughout the estrous cycle Liu, Yi; Ma, Xiaofang; Chen, Xuhong Experimental and Therapeutic Medicine https://doi.org/10.3892/etm.2020.8416	journal	January 2020

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
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SUMOylation
Ubc9
X-ray crystallography

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