X-ray structure of human stromelysin catalytic domain complexed with nonpeptide inhibitors: Implications for inhibitor selectivity

Alexander G. Pavlovsky, Mark G. Williams, Qi Zhuang Ye, Daniel F. Ortwine, Claude F. Purchase, Andrew D. White, V. Dhanaraj, Bruce D. Roth, Linda L. Johnson, Donald Hupe, Christine Humblet, Tom L. Blundell

Research output: Contribution to journalArticle

76 Scopus citations

Abstract

Effective inhibitors of matrix metalloproteinases (MMPs), a family of connective tissue-degrading enzymes, could be useful for the treatment of diseases such as cancer, multiple sclerosis, and arthritis. Many of the known MMP inhibitors are derived from peptide substrates, with high potency in vitro but little selectivity among MMPs and poor bioavailability. We have discovered nonpeptidic MMP inhibitors with improved properties, and report here the crystal structures of human stromelysin-1 catalytic domain (SCD) complexed with four of these inhibitors. The structures were determined and refined at resolutions ranging from 1.64 to 2.0 Å. Each inhibitor binds in the active site of SCD such that a bulky diphenyl piperidine moiety penetrates a deep, predominantly hydrophobic S1/' pocket. The active site structure of the SCD is similar in all four inhibitor complexes, but differs substantially from the peptide hydroxamate complex, which has a smaller side chain bound in the S1/' pocket. The largest differences occur in the loop forming the 'top' of this pocket. The occupation of these nonpeptidic inhibitors in the S1/' pocket provides a structural basis to explain their selectivity among MMPs. An analysis of the unique binding mode predicts structural modifications to design improved MMP inhibitors.

Original languageEnglish (US)
Pages (from-to)1455-1462
Number of pages8
JournalProtein Science
Volume8
Issue number7
DOIs
StatePublished - Jan 1 1999
Externally publishedYes

Keywords

  • Drug design
  • MMP-3
  • Matrix metalloproteinase
  • Nonpeptide inhibitors
  • X-ray crystallography

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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  • Cite this

    Pavlovsky, A. G., Williams, M. G., Ye, Q. Z., Ortwine, D. F., Purchase, C. F., White, A. D., Dhanaraj, V., Roth, B. D., Johnson, L. L., Hupe, D., Humblet, C., & Blundell, T. L. (1999). X-ray structure of human stromelysin catalytic domain complexed with nonpeptide inhibitors: Implications for inhibitor selectivity. Protein Science, 8(7), 1455-1462. https://doi.org/10.1110/ps.8.7.1455