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. 1991 Aug 15;88(16):6916–6920. doi: 10.1073/pnas.88.16.6916

Leucine aminopeptidase: bestatin inhibition and a model for enzyme-catalyzed peptide hydrolysis.

S K Burley 1, P R David 1, W N Lipscomb 1
PMCID: PMC52204  PMID: 1871107

Abstract

The three-dimensional structures of native bovine lens leucine aminopeptidase (EC 3.4.11.1) and its complex with bestatin, a slow-binding inhibitor, have been solved and exhaustively refined. The mode of binding of bestatin to leucine aminopeptidase may be similar to that of a tetrahedral intermediate that is thought to form during peptide bond hydrolysis. Bestatin binds in the active site with its alpha-amino group and hydroxyl group coordinated to the zinc ion located in the readily exchangeable divalent cation binding site. Its phenylalanyl side chain is stabilized by van der Waals interactions with Met-270, Thr-359, Gly-362, Ala-451, and Met-454, which appear to form a terminal hydrophobic pocket. The leucyl side chain binds in another hydrophobic cleft lined by Asn-330, Ala-333, and Ile-421. Hydrogen bonds involving active site residues Lys-262, Asp-273, Gly-360, and Leu-362 are responsible for stabilizing the backbone nitrogen and oxygen atoms of bestatin. The mode of bestatin inhibition of leucine aminopeptidase is discussed and correlated with biochemical studies of bestatin analogues. In addition, features of a mechanism of catalysis of peptide hydrolysis by leucine aminopeptidase are discussed.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

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