Crystal structure of a peptidyl-dipeptidase K-26-DCP from Actinomycete in complex with its natural inhibitor.

Geoffrey Masuyer,K Ravi Acharya,Glenna J Kramer,Gyles E Cozier,Brian O Bachmann

doi:10.1111/febs.13928

Geoffrey Masuyer, K Ravi Acharya + Show 3 more

Open Access

https://doi.org/10.1111/febs.13928

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Journal: FEBS Journal	Publication Date: Nov 6, 2016
Citations: 7	License type: CC BY 4.0

Affiliation: University of Bath, Vanderbilt University

Abstract

Several soil‐derived Actinobacteria produce secondary metabolites that are proven specific and potent inhibitors of the human angiotensin‐I‐converting enzyme (ACE), a key target for the modulation of hypertension through its role in the renin–angiotensin–aldosterone system. K‐26‐DCP is a zinc dipeptidyl carboxypeptidase (DCP) produced by Astrosporangium hypotensionis, and an ancestral homologue of ACE. Here we report the high‐resolution crystal structures of K‐26‐DCP and of its complex with the natural microbial tripeptide product K‐26. The experimental results provide the structural basis for better understanding the specificity of K‐26 for human ACE over bacterial DCPs.DatabaseStructural data are available in the PDB under the accession numbers 5L43 and 5L44.

Highlights

The M3 family of metalloproteases belong to the gluzincin class of enzymes (MEROPS database) [1], which present a single catalytic zinc ion coordinated by the conserved HEXGH-binding motif
Our analysis provides the structural basis of K-26 recognition by the two homologues dipeptidyl carboxypeptidase (DCP) and angiotensin-I-converting enzyme (ACE)
The crystal structures of the DCP from A. hypotensionis with and without a bound ligand were determined at 1.8 A resolution (Table 1)

Summary

Introduction

The M3 family of metalloproteases belong to the gluzincin class of enzymes (MEROPS database) [1], which present a single catalytic zinc ion coordinated by the conserved HEXGH-binding motif. Members of this family are widespread across all organisms, from bacterial dipeptidyl carboxypeptidase (DCP) [2] to the mammalian thimet oligopeptidase [3] and neurolysin [4]. The peptide is cleaved between residues P1 and P01, with residues Pn binding in subsites Sn. Astrosporangium hypotensionis is a soil bacteria of the actinomycete family that produces a zinc peptidase, K-26-DCP, which has strong sequence similarity with its E. coli homologue (E. coli DCP, 47% sequence identity) [9]. Our analysis provides the structural basis of K-26 recognition by the two homologues DCP and ACE

Results and Discussion

Experimental procedures

Conflict of interest