Journal of Computer-Aided Molecular Design

, Volume 17, Issue 9, pp 551–565

Modeling of enzyme–substrate complexes for the metalloproteases MMP-3, ADAM-9 and ADAM-10

  • Sergio Manzetti
  • Daniel R. McCulloch
  • Adrian C. Herington
  • David van der Spoel
Article

DOI: 10.1023/B:JCAM.0000005765.13637.38

Cite this article as:
Manzetti, S., McCulloch, D.R., Herington, A.C. et al. J Comput Aided Mol Des (2003) 17: 551. doi:10.1023/B:JCAM.0000005765.13637.38

Abstract

The matrix metalloproteases (MMPs) and the ADAMs (A Disintegrin And Metalloprotease domain) are proteolytic enzyme families containing a catalytic zinc ion, that are implicated in a variety of normal and pathological processes involving tissue remodeling and cancer. Synthetic MMP inhibitors have been designed for applications in pathological situations. However, a greater understanding of substrate binding and the catalytic mechanism is required so that more effective and selective inhibitors may be developed for both experimental and clinical purposes. By modeling a natural substrate spanning P4-P4′ in complex with the catalytic domains, we aim to compare substrate-specificities between Stromelysin-1 (MMP-3), ADAM-9 and ADAM–10, with the aid of molecular dynamics simulations. Our results show that the substrate retains a favourable antiparallel beta-sheet conformation on the P-side in addition to the well-known orientation of the P′-region of the scissile bond, and that the primary substrate selectivity is dominated by the sidechains in the S1′ pocket and the S2/S3 region. ADAM-9 has a hydrophobic residue as the central determinant in the S1′ pocket, while ADAM-10 has an amphiphilic residue, which suggests a different primary specificity. The S2/S3 pocket is largely hydrophobic in all three enzymes. Inspired by our molecular dynamics calculations and supported by a large body of literature, we propose a novel, hypothetical, catalytic mechanism where the Zn-ion polarizes the oxygens from the catalytic glutamate to form a nucleophile, leading to a tetrahedral oxyanion anhydride transition state.

ADAM (A Disintegrin And Metalloprotease domain)cancercatalytic mechanismGROMACSmatrix metalloproteases (MMPs)substrate specificity

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Sergio Manzetti
    • 1
    • 2
    • 3
    • 4
  • Daniel R. McCulloch
    • 1
  • Adrian C. Herington
    • 1
  • David van der Spoel
    • 5
  1. 1.Centre for Molecular Biotechnology, School of Life SciencesQueensland University of TechnologyBrisbaneAustralia
  2. 2.Proinformatix.com, Øvre Lippestad GaardTomterNorway
  3. 3.Biozentrum, University of BaselBaselSwitzerland
  4. 4.Institute of Cellular and Molecular Biology, Biology DepartmentUniversity of OsloBlindernveien, OsloNorway
  5. 5.Department of Cell and Molecular BiologyBiomedical CenterUppsalaSweden