Molecular Biotechnology

, Volume 24, Issue 2, pp 157–202 | Cite as

Structural aspects of the metzincin clan of metalloendopeptidases

  • F. Xavier Gomis-RüthEmail author


Metalloendopeptidases are present across all kingdoms of living organisms; they are ubiquitous and widely involved in metabolism regulation through their ability either to extensively degrade proteins or to selectively hydrolyze specific peptide bonds. They must be subjected to exquisite spatial and temporal control to prevent this vast potential from becoming destructive. These enzymes are mostly zinc-dependent and the majority of them, named zincins, possess a short consensus sequence, HEXXH, with the two histidines acting as ligands of the catalytic zinc and the glutamate as the general base. A subclass of the zincins is characterized by a C-terminally elongated motif, HEXXHXXGXXH/D, with an additional strictly conserved glycine and a third zinc-binding histidine or aspartate. Currently, representative three-dimensional structures of six different proteinase families bearing this motif show, despite low sequence similarity, comparable overall topology. This includes a substrate-binding crevice, which subdivides the enzyme moiety into an upper and a lower subdomain. A common five-stranded β-sheet and two α-helices are always found in the upper subdomain. The second of these helices encompasses the first half of the elongated consensus sequence and is therefore termed the active-site helix. Other shared characteristics are an invariant methionine-containing Met-turn beneath the catalytic metal and a further C-terminal helix in the lower subdomain. All these structural features identify the metzincin clan of metalloendopeptidases. This clan is reviewed from a structural point of view, based on the reported structures of representative members of the astacins, adamalysins, serralysins, matrixins, snapalysins, and leishmanolysins, and of inhibited forms, either by specific endogenous protein inhibitors or by zymogenic pro-domains. Moreover, newly available genomic sequences have unveiled novel putative metzincin families and new hypothetical members of existing ones.

Index Entries

Zinc metalloproteinase metzincin ADAM astacin serralysin matrix metalloproteinase MMP vertebrate collagenase leishmanolysin adamalysin reprolysin three-dimensional structure X-ray crystal structure metalloendopeptidase 



ATP-binding cassette


a disintegrin and metalloprotease


ADAM with thrombospondin-like repeats


Bacteroides fragilis enterotoxin


bone morphogenetic protein


protein domain present in complement Clr/Cls, Uegf, and BMP-1


extracellular matrix


epidermal growth factor


gamete lytic enzyme


glycosyl phosphatidylinositol


human immunodeficiency virus


hydrogenase-maturating endopeptidase B


late somatic gene 2


meprin and TRAF homology domain


domain present in meprin, A-5 protein and tyrosine phosphatase μ


metalloprotease-like, disintegrin-like, and cysteine-rich proteins




matrix metalloproteinase alias vertebrate collagenase and matrixin




membrane-type MMP


open-reading frame


pregnancy-associated plasma protein


Protein Data Bank access code for three-dimensional structure coordinates


reversion-inducing cysteine-rich protein with Kazal motifs

S1, S2, and P1, P2

denote protease activesite cleft and substrate subsites, respectively, N-terminally of the scissile peptide bond, S1′, S2′, and P1′, P2′, at the C-terminus of the scission, in accordance with ref. 27


S. caespitosus neutral protease


snake venom metalloproteinase


tumor-necrosis factor αconverting enzyme


transforming growth factor


tissue inhibitor of metalloproteinases


Volvox metalloproteinase


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© Humana Press Inc 2003

Authors and Affiliations

  1. 1.Institut de Biologia Molecular de BarcelonaC.I.D.—C.S.I.C.BarcelonaSpain

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