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An unexpected switch in peptide binding mode: from simulation to substrate specificity.

Ursula Kahler1, Julian E Fuchs1, Peter Goettig2

  • 1a Faculty of Chemistry and Pharmacy, Institute of General, Inorganic and Theoretical Chemistry , University Innsbruck , Innrain 82, Innsbruck A-6020 , Austria.

Journal of Biomolecular Structure & Dynamics
|December 7, 2017
PubMed
Summary
This summary is machine-generated.

Molecular dynamics simulations revealed kallikrein-related peptidase 7 (KLK7) peptide substrates can adopt an alternative binding pose. This unexpected shift to the prime side may advance drug design for KLK7-related diseases.

Keywords:
chymotrypsin-like serine proteasedrug designin silico mutationpeptide recognitionspecificity subsites

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Computational Chemistry

Background:

  • Kallikrein-related peptidase 7 (KLK7) is implicated in skin diseases and cancer.
  • Understanding KLK7 substrate binding is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the binding dynamics and modes of peptide substrates with KLK7.
  • To characterize a newly observed binding conformation and its implications for KLK7 function.

Main Methods:

  • Ten microsecond molecular dynamics (MD) simulations of a KLK7-peptide complex.
  • Analysis of binding pose transitions, residue interactions, and solvent accessibility.
  • In silico mutagenesis to assess prime side specificity.

Main Results:

  • A spontaneous, stable transition to an alternative binding pose was observed after 2 microseconds.
  • The peptide substrate rotated 180° around the P1 residue, occupying the prime side.
  • The alternative binding mode shares similarities with inhibitor-bound KLK structures.

Conclusions:

  • This study presents the first microsecond-timescale simulation of a kallikrein protease.
  • Unexplored prime side interactions of KLK7 were characterized.
  • Findings are expected to aid rational inhibitor design for KLK7, a significant drug target.