Matrix metalloproteinases: fold and function of their catalytic domains.
Matrix metalloproteinases (MMPs) are zinc-dependent protein and peptide hydrolases. They have been almost exclusively studied in vertebrates and 23 paralogs are present in humans. They are widely involved in metabolism regulation through both extensive protein degradation and selective peptide-bond hydrolysis. If MMPs are not subjected to exquisite spatial and temporal control, they become destructive, which can lead to pathologies such as arthritis, inflammation, and cancer. The main therapeutic strategy to combat the dysregulation of MMPs is the design of drugs to target their catalytic domains, for which purpose detailed structural knowledge is essential. The catalytic domains of 13 MMPs have been structurally analyzed so far and they belong to the "metzincin" clan of metalloendopeptidases. These compact, spherical, approximately 165-residue molecules are divided by a shallow substrate-binding crevice into an upper and a lower sub-domain. The molecules have an extended zinc-binding motif, HEXXHXXGXXH, which contains three zinc-binding histidines and a glutamate that acts as a general base/acid during catalysis. In addition, a conserved methionine lying within a "Met-turn" provides a hydrophobic base for the zinc-binding site. Further earmarks of MMPs are three alpha-helices and a five-stranded beta-sheet, as well as at least two calcium sites and a second zinc site with structural functions. Most MMPs are secreted as inactive zymogens with an N-terminal approximately 80-residue pro-domain, which folds into a three-helix globular domain and inhibits the catalytic zinc through a cysteine imbedded in a conserved motif, PRCGXPD. Removal of the pro-domain enables access of a catalytic solvent molecule and substrate molecules to the active-site cleft, which harbors a hydrophobic S(1')-pocket as main determinant of specificity. Together with the catalytic zinc ion, this pocket has been targeted since the onset of drug development against MMPs. However, the inability of first- and second-generation inhibitors to distinguish between different MMPs led to failures in clinical trials. More recent approaches have produced highly specific inhibitors to tackle selected MMPs, thus anticipating the development of more successful drugs in the near future. Further strategies should include the detailed structural characterization of the remaining ten MMPs to assist in achieving higher drug selectivity. In this review, we discuss the general architecture of MMP catalytic domains and its implication in function, zymogenic activation, and drug design.
Tallant
Cynthia
C
Proteolysis Lab, Molecular Biology Institute of Barcelona, CSIC, Barcelona Science Park, Helix Building, c/Baldiri Reixac, 15-21, E-08028 Barcelona, Spain.
Marrero
Aniebrys
A
Gomis-Rüth
F Xavier
FX
D000818:Animals; D020134:Catalytic Domain; D004792:Enzyme Precursors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D020782:Matrix Metalloproteinases / Q000737:chemistry* / Q000145:classification / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D017433:Protein Structure, Secondary; D015032:Zinc / Q000378:metabolism
D004792:Enzyme Precursors; D010455:Peptides; D020782:Matrix Metalloproteinases; D015032:Zinc