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Changes in zinc ligation promote remodeling of the active site in the zinc hydrolase superfamily

Wouters, Merridee A. and Husain, Ahsan 2001, Changes in zinc ligation promote remodeling of the active site in the zinc hydrolase superfamily, Journal of molecular biology, vol. 314, no. 5, pp. 1191-1207, doi: 10.1006/jmbi.2000.5161.

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Title Changes in zinc ligation promote remodeling of the active site in the zinc hydrolase superfamily
Author(s) Wouters, Merridee A.
Husain, Ahsan
Journal name Journal of molecular biology
Volume number 314
Issue number 5
Start page 1191
End page 1207
Total pages 17
Publisher Academic Press
Place of publication London, England
Publication date 2001-12-14
ISSN 0022-2836
1089-8638
Keyword(s) zinc metalloprotease
carboxypeptidase A
leucine aminopeptidase
molecular evolution
co-catalytic
Summary The zinc hydrolase superfamily is a group of divergently related proteins that are predominantly enzymes with a zinc-based catalytic mechanism. The common structural scaffold of the superfamily consists of an eight-stranded β-sheet flanked by six α-helices. Previous analyses, while acknowledging the likely divergent origins of leucine aminopeptidase, carboxypeptidase A and the co-catalytic enzymes of the metallopeptidase H clan based on their structural scaffolds, have failed to find any homology between the active sites in leucine aminopeptidase and the metallopeptidase H clan enzymes. Here we show that these two groups of co-catalytic enzymes have overlapping dizinc centers where one of the two zinc atoms is conserved in each group. Carboxypeptidase A and leucine aminopeptidase, on the other hand, no longer share any homologous zinc-binding sites. At least three catalytic zinc-binding sites have existed in the structural scaffold over the period of history defined by available structures. Comparison of enzyme-inhibitor complexes show that major remodeling of the substrate-binding site has occurred in association with each change in zinc ligation in the binding site. These changes involve re-registration and re-orientation of the substrate. Some residues important to the catalytic mechanism are not conserved amongst members. We discuss how molecules acting in trans may have facilitated the mutation of catalytically important residues in the active site in this group.
Language eng
DOI 10.1006/jmbi.2000.5161
Field of Research 060199 Biochemistry and Cell Biology not elsewhere classified
Socio Economic Objective 970106 Expanding Knowledge in the Biological Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2001, Elsevier
Persistent URL http://hdl.handle.net/10536/DRO/DU:30038992

Document type: Journal Article
Collection: School of Life and Environmental Sciences
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