Structure of the catalytic domain of human fibroblast collagenase complexed with an inhibitor

Nat Struct Biol. 1994 Feb;1(2):106-10. doi: 10.1038/nsb0294-106.

Abstract

In rheumatoid and osteoarthritis, degradation of articular cartilage is mediated by the matrix metalloproteinases collagenase, stromelysin and gelatinase. The key event in this process is the cleavage of triple helical collagen by collagenase. We have determined the crystal structure of the catalytic domain of human recombinant fibroblast collagenase complexed with a synthetic inhibitor at 2.2 A resolution. The protein fold is similar to the amino termini of the zinc endopeptidases astacin thermolysin and elastase despite a lack of primary sequence homology. The conformation of the bound inhibitor provides a molecular basis for the design of inhibitors of collagenase and other matrix metalloproteinases. Such inhibitors should be useful in the treatment of a variety of diseases including arthritis and cancer.

MeSH terms

  • Amino Acid Sequence
  • Arthritis, Rheumatoid / metabolism
  • Binding Sites
  • Cartilage / metabolism
  • Catalysis
  • Collagen / chemistry
  • Collagen / metabolism
  • Collagenases / chemistry*
  • Collagenases / genetics
  • Fibroblasts / enzymology
  • Humans
  • In Vitro Techniques
  • Matrix Metalloproteinase Inhibitors*
  • Metalloendopeptidases / antagonists & inhibitors
  • Metalloendopeptidases / chemistry
  • Metalloendopeptidases / genetics
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Structure
  • Osteoarthritis / metabolism
  • Protein Conformation
  • Protein Folding
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Zinc / chemistry

Substances

  • Matrix Metalloproteinase Inhibitors
  • Recombinant Proteins
  • Collagen
  • Collagenases
  • Metalloendopeptidases
  • Zinc