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Critical Non-Covalent Binding Intermediate for an Allosteric Covalent Inhibitor of SUMO E1

Shristi Pawnikar1, Apurba Bhattarai1, S Xiaohu Ouyang2

  • 1Center for Computational Biology and Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 66047, United States.

The Journal of Physical Chemistry Letters
|March 10, 2023
PubMed

Insights

Researchers uncovered a key non-covalent binding intermediate in SUMO E1 inhibition using molecular dynamics simulations. This finding reconciles structural data with drug activity, advancing immuno-oncology drug development for cancer.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Computational Chemistry

Background:

  • Post-translational modifications by small ubiquitin-like modifiers (SUMOs) are crucial cellular processes often dysregulated in cancer.
  • The SUMO E1 enzyme is a promising target for immuno-oncology therapies.
  • COH000 is a specific allosteric covalent inhibitor of SUMO E1, but its binding mechanism has been unclear.

Purpose of the Study:

  • To investigate the non-covalent interactions between COH000 and SUMO E1 during inhibitor dissociation.
  • To resolve discrepancies between X-ray crystallography data and structure-activity relationship (SAR) data for COH000 analogues.
  • To elucidate the allosteric inhibition mechanism of the SUMO E1 complex.

Main Methods:

  • Ligand Gaussian accelerated molecular dynamics (LiGaMD) simulations were employed to study inhibitor dissociation.
  • Biochemical experiments were conducted to validate simulation findings.
  • Analysis of protein-ligand interactions and binding conformations.

Main Results:

  • LiGaMD simulations identified a critical low-energy non-covalent binding intermediate conformation of COH000.
  • This intermediate conformation aligns exceptionally well with published and new SAR data for COH000 analogues.
  • The identified intermediate explains the previously observed inconsistencies with the X-ray structure.

Conclusions:

  • A critical non-covalent binding intermediate is essential for the allosteric inhibition of the SUMO E1 complex by COH000.
  • This study reconciles structural and SAR data, providing a more accurate understanding of COH000's mechanism of action.
  • The findings offer valuable insights for the design of novel SUMO E1 inhibitors in cancer therapy.

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