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Title

Architecture and function of metallopeptidase catalytic domains

AuthorsCerdà-Costa, Núria CSIC; Gomis-Rüth, F. Xavier CSIC ORCID
KeywordsMetalloprotease
Metalloproteinase
Matrix metalloproteases, Astacins
Adamalysins
ADAM
Metzincin clan
Hydrolytic enzymes
Active-site cleft
Serralysins
Catalytic domains
Structural biochemistry
Issue Date2014
PublisherWiley-Blackwell
CitationProtein Science 23(2): 123-144 (2014)
AbstractThe cleavage of peptide bonds bymetallopeptidases (MPs) is essential for life. These ubiquitous enzymes participate in allmajor physiological processes, and so their deregulation leads to diseases ranging fromcancer andmetastasis, inflammation, and microbial infection to neurological insults and cardiovascular disorders.MPs cleave their substrateswithout a covalent intermediate in a singlestep reaction involving a solventmolecule, a general base/acid, and a mono- or dinuclear catalyticmetal site.MostmonometallicMPs comprise a short metal-bindingmotif (HEXXH), which includes two metalbinding histidines and a general base/acid glutamate, and they are grouped into the zincin tribe ofMPs. The latter divides mainly into the gluzincin andmetzincin clans. Metzincins consist of globular ~130-270- residue catalytic domains,which are usually preceded byN-terminal pro-segments, typically required for folding and latency maintenance. The catalytic domains are often followed byC-terminal domains for substrate recognition and other protein-protein interactions, anchoring tomembranes, oligomerization, and compartmentalization.Metzincin catalytic domains consist of a structurally conserved N-terminal subdomain spanning a five-stranded b-sheet, a backing helix, and an active-site helix. The latter contains most of the metal-binding motif, which is here characteristically extended to HEXXHXXGXX(H,D). Downstream C-terminal subdomains are generally shorter, differmore amongmetzincins, and mainly share a conserved loop-the Met-turn-and a C-terminal helix. The accumulated structural data frommore than 300 deposited structures of the 12 currently characterize dmetzincin families reviewed here provide detailed knowledge of the molecular features of their catalytic domains, help in our understanding of theirworking mechanisms, and form the basis for the design of novel drugs. © 2013 The Protein Society.
Publisher version (URL)http://dx.doi.org/10.1002/pro.2400
URIhttp://hdl.handle.net/10261/101850
DOI10.1002/pro.2400
Identifiersdoi: 10.1002/pro.2400
issn: 1469-896X
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