Structure of the Catalytic Domain of Fibroblast Collagenase Complexed with an Inhibitor

TLDR

Collagenase, a zinc‑dependent endoproteinase of the matrix metalloproteinase family, participates in connective tissue remodeling, shares structural homology with bacterial thermolysin and crayfish astacin, and its aberrant regulation is linked to various pathologies. The study aims to detail protein‑inhibitor interactions in collagenase to facilitate the design of selective MMP inhibitors and to probe MMP function in disease. The authors determined the 2.4‑Å crystal structure of collagenase bound to an inhibitor, revealing the protein‑inhibitor interactions. The crystal structure shows that, besides the catalytic zinc, a second zinc ion and a calcium ion stabilize collagenase’s tertiary structure.

Abstract

Collagenase is a zinc-dependent endoproteinase and is a member of the matrix metalloproteinase (MMP) family of enzymes. The MMPs participate in connective tissue remodeling events and aberrant regulation has been associated with several pathologies. The 2.4 angstrom resolution structure of the inhibited enzyme revealed that, in addition to the catalytic zinc, there is a second zinc ion and a calcium ion which play a major role in stabilizing the tertiary structure of collagenase. Despite scant sequence homology, collagenase shares structural homology with two other endoproteinases, bacterial thermolysin and crayfish astacin. The detailed description of protein-inhibitor interactions present in the structure will aid in the design of compounds that selectively inhibit individual members of the MMP family. Such inhibitors will be useful in examining the function of MMPs in pathological processes.