X-ray structure of a hydroxamate inhibitor complex of stromelysin catalytic domain and its comparison with members of the zinc metalloproteinase superfamily

V. Dhanaraj, Q. Z. Ye, L. L. Johnson, D. J. Hupe, D. F. Ortwine, J. B. Dunbar, J. R. Rubin, A. Pavlovsky, C. Humblet, T. L. Blundell

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110 Scopus citations

Abstract

Background: Stromelysin belongs to a family of zinc-dependent endopeptidases referred to as matrix metalloproteinases (MMPs, matrixins) because of their capacity for selective degradation of various components of the extracellular matrix. Matrixins play key roles in diseases as diverse as arthritis and cancer and hence are important targets for therapeutic intervention. Results: The crystal structure of the stromelysin catalytic domain (SCD) with bound hydroxamate inhibitor, solved by multiple isomorphous replacement, shows a deep S1′ specificity pocket which explains differences in inhibitor binding between the collagenases and stromelysin. The binding of calcium ions by loops at the two ends of a β-strand which marks the boundary of the active site provides a structural rationale for the importance of these cations for stability and catalytic activity. Major differences between the matrixins are clustered in two regions forming the entrance to the active site and hence may be determinants of substrate selectivity. Conclusions: Structural comparisons of SCD with representative members of the metalloproteinase superfamily clearly highlight the conservation of key secondary structural elements, in spite of major variations in the sequences including insertions and deletions of functional domains. However, the three-dimensional structure of SCD, which is generally closely related to the collagenases, shows significant differences not only in the peripheral regions but also in the specificity pockets; these latter differences should facilitate the rational design of specific inhibitors.

Original languageEnglish (US)
Pages (from-to)375-386
Number of pages12
JournalStructure
Volume4
Issue number4
DOIs
StatePublished - Jan 1 1996

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Keywords

  • Hydroxamate inhibitor
  • Matrix metalloproteinase-3 (MMP-3)
  • Metzincin
  • Stromelysin
  • Zinc-dependent metalloproteinase superfamily

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Dhanaraj, V., Ye, Q. Z., Johnson, L. L., Hupe, D. J., Ortwine, D. F., Dunbar, J. B., Rubin, J. R., Pavlovsky, A., Humblet, C., & Blundell, T. L. (1996). X-ray structure of a hydroxamate inhibitor complex of stromelysin catalytic domain and its comparison with members of the zinc metalloproteinase superfamily. Structure, 4(4), 375-386. https://doi.org/10.1016/S0969-2126(96)00043-3