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Critical Non-Covalent Binding Intermediate for an Allosteric Covalent Inhibitor of SUMO E1
Pawnikar, Shristi Bhattarai, Apurba Ouyang, S. Xiaohu Vega, Ramir Chen, Yuan Miao, Yinglong
Pawnikar, Shristi
Bhattarai, Apurba
Ouyang, S. Xiaohu
Vega, Ramir
Chen, Yuan
Miao, Yinglong
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Abstract
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.
Description
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Physical Chemistry Letters, copyright © Copyright © 2023 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.jpclett.3c00253.
Date
2023-03-10
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American Chemical Society
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Keywords
SUMO E1, Allosteric inhibitor, Ligand Gaussian accelerated molecular dynamics, Structure-activity-relationship, SUMOylation
Citation
Pawnikar, S., Bhattarai, A., Ouyang, S. X., Vega, R., Chen, Y., & Miao, Y. (2023). Critical Non-Covalent Binding Intermediate for an Allosteric Covalent Inhibitor of SUMO E1. The journal of physical chemistry letters, 14(11), 2792–2799. https://doi.org/10.1021/acs.jpclett.3c00253