Post-translational modifications by small ubiquitin-like modifiers (SUMOs) are dysregulated in many types of cancers. The SUMO E1 enzyme has recently been suggested as a new immuno-oncology target. COH000 was recently identified as a highly specific allosteric covalent inhibitor of SUMO E1. However, a marked discrepancy was found between the X-ray structure of the covalent COH000-bound SUMO E1 complex and the available structure-activity relationship (SAR) data of inhibitor analogues due to unresolved noncovalent protein-ligand interactions. Here, we have investigated noncovalent interactions between COH000 and SUMO E1 during inhibitor dissociation through novel Ligand Gaussian accelerated molecular dynamics (LiGaMD) simulations. Our simulations have identified a critical low-energy non-covalent binding intermediate conformation of COH000 that agreed excellently with published and new SAR data of the COH000 analogues, which were otherwise inconsistent with the X-ray structure. Altogether, our biochemical experiments and LiGaMD simulations have uncovered a critical non-covalent binding intermediate during allosteric inhibition of the SUMO E1 complex.

01 Feb 2019·Cell Chemical BiologyQ1 · BIOLOGY

Allosteric Inhibition of Ubiquitin-like Modifications by a Class of Inhibitor of SUMO-Activating Enzyme

Q1 · BIOLOGY

Article

Author: Samuels, Eric R ; Divlianska, Daniela B ; Fakih, Marwan ; Chung, Thomas D Y ; Ouyang, S Xiaohu ; Colayco, Sharon A ; Du, Li ; Li, Yi-Jia ; Sergienko, Eduard ; Miao, Yunan ; Lee, Terry D ; Aldana-Masangkay, Grace ; Bobkova, Ekaterina V ; Vega, Ramir ; Li, Baozong ; Chen, Yuan ; Wang, Jianghai

Ubiquitin-like (Ubl) post-translational modifications are potential targets for therapeutics. However, the only known mechanism for inhibiting a Ubl-activating enzyme is through targeting its ATP-binding site. Here we identify an allosteric inhibitory site in the small ubiquitin-like modifier (SUMO)-activating enzyme (E1). This site was unexpected because both it and analogous sites are deeply buried in all previously solved structures of E1s of ubiquitin-like modifiers (Ubl). The inhibitor not only suppresses SUMO E1 activity, but also enhances its degradation in vivo, presumably due to a conformational change induced by the compound. In addition, the lead compound increased the expression of miR-34b and reduced c-Myc levels in lymphoma and colorectal cancer cell lines and a colorectal cancer xenograft mouse model. Identification of this first-in-class inhibitor of SUMO E1 is a major advance in modulating Ubl modifications for therapeutic aims.

Nature CommunicationsQ1 · CROSS-FIELD

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

Q1 · CROSS-FIELD

ArticleOA

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

AbstractE1 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.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	United States	The Medical University of South Carolina	-
Colorectal Cancer	Discovery	United States	City of Hope National Medical Center	-

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