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Mechanistic Insights into the Mechanism of Allosteric Inhibition of Ubiquitin-Specific Protease 7 (USP7)

Xuebin Wang1, Ning Liu2, Nuan Li3

  • 1Department of Pharmacy, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200062, China.

Biomolecules
|June 26, 2025
PubMed

Insights

Allosteric inhibitor binding increases USP7 enzyme flexibility, disrupting its catalytic triad and hindering ubiquitin accessibility. This dynamic shift effectively inhibits USP7 activity, offering insights into deubiquitinase enzyme modulation.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Enzymology

Background:

  • Ubiquitin-specific protease 7 (USP7) is a deubiquitinase enzyme crucial in oncogenic pathways and human diseases.
  • USP7 exists in distinct conformations (apo, inhibitor-bound, Ub-bound), but the dynamics of allosteric inhibition are not fully understood.

Purpose of the Study:

  • To investigate the dynamic effects of allosteric inhibitor binding on USP7 using molecular dynamics simulations.
  • To elucidate the mechanisms by which allosteric inhibitors modulate USP7 activity.

Main Methods:

  • Multiple replica molecular dynamics simulations were employed to study USP7 dynamics.
  • Analysis included conformational changes, domain flexibility, catalytic triad alignment, and intra-domain communication.

Main Results:

  • Ubiquitin binding stabilizes USP7, whereas allosteric inhibitor binding increases flexibility in the fingers and palm domains.
  • Allosteric inhibitors impede Ub accessibility by restraining the C-terminal Ub binding site and disrupt the catalytic triad alignment.
  • Enhanced intra-domain communication within the fingers domain was observed upon allosteric inhibitor binding.

Conclusions:

  • Allosteric inhibitor binding induces a dynamic conformational shift in USP7, disrupting its catalytic activity.
  • This study reveals USP7 allosteric modulation mechanisms, impacting enzyme function through dynamic changes.
Keywords:
allosteric communicationallosteric inhibitionconformational dynamicsmolecular dynamics simulationsprotein–protein interactions

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