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

journal contribution
posted on 2001-12-14, 00:00 authored by Merridee Wouters, A Husain
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.

History

Journal

Journal of molecular biology

Volume

314

Issue

5

Pagination

1191 - 1207

Publisher

Academic Press

Location

London, England

ISSN

0022-2836

eISSN

1089-8638

Language

eng

Publication classification

C1.1 Refereed article in a scholarly journal

Copyright notice

2001, Elsevier

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