Critical Non-Covalent Binding Intermediate for an Allosteric Covalent Inhibitor of SUMO E1.
Shristi PawnikarApurba BhattaraiS Xiaohu OuyangRamir VegaYuan ChenYinglong MiaoPublished in: The journal of physical chemistry letters (2023)
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.
Keyphrases
- molecular dynamics
- small molecule
- structure activity relationship
- density functional theory
- binding protein
- high resolution
- electronic health record
- molecular docking
- palliative care
- monte carlo
- dna binding
- randomized controlled trial
- protein protein
- magnetic resonance imaging
- dual energy
- transcription factor
- data analysis
- atomic force microscopy
- deep learning