Structure of human aspartyl aminopeptidase complexed with substrate analogue: insight into catalytic mechanism, substrate specificity and M18 peptidase family.Reportar como inadecuado




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Reference: Chaikuad, A, Pilka, ES, De Riso, A et al., (2012). Structure of human aspartyl aminopeptidase complexed with substrate analogue: insight into catalytic mechanism, substrate specificity and M18 peptidase family. BMC structural biology, 12 (1), 14.Citable link to this page:

 

Structure of human aspartyl aminopeptidase complexed with substrate analogue: insight into catalytic mechanism, substrate specificity and M18 peptidase family.

Abstract: BACKGROUND: Aspartyl aminopeptidase (DNPEP), with specificity towards an acidic amino acid at the N-terminus, is the only mammalian member among the poorly understood M18 peptidases. DNPEP has implicated roles in protein and peptide metabolism, as well as the renin-angiotensin system in blood pressure regulation. Despite previous enzyme and substrate characterization, structural details of DNPEP regarding ligand recognition and catalytic mechanism remain to be delineated. RESULTS: The crystal structure of human DNPEP complexed with zinc and a substrate analogue aspartate-β-hydroxamate reveals a dodecameric machinery built by domain-swapped dimers, in agreement with electron microscopy data. A structural comparison with bacterial homologues identifies unifying catalytic features among the poorly understood M18 enzymes. The bound ligands in the active site also reveal the coordination mode of the binuclear zinc centre and a substrate specificity pocket for acidic amino acids. CONCLUSIONS: The DNPEP structure provides a molecular framework to understand its catalysis that is mediated by active site loop swapping, a mechanism likely adopted in other M18 and M42 metallopeptidases that form dodecameric complexes as a self-compartmentalization strategy. Small differences in the substrate binding pocket such as shape and positive charges, the latter conferred by a basic lysine residue, further provide the key to distinguishing substrate preference. Together, the structural knowledge will aid in the development of enzyme-/family-specific aminopeptidase inhibitors.

Peer Review status:Peer reviewedPublication status:PublishedVersion:Publisher's version Funder: Canadian Institutes of Health Research   Funder: Canadian Foundation for Innovation   Funder: Genome Canada   Funder: GlaxoSmithKline   Funder: Karolinska Institute   Funder: Knut and Alice Wallenberg Foundation   Funder: Ontario Innovation Trust   Funder: Ministry of Research and Innovation, Ontario   Funder: Merck and Co Inc   Funder: Novartis Research Foundation   Funder: Swedish Governmental Agency for Innovation Systems   Funder: Swedish Foundation for Strategic Research   Funder: Wellcome Trust   Notes:© 2012 Chaikuad et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Bibliographic Details

Publisher: BioMed Central Ltd.

Publisher Website: http://www.biomedcentral.com/

Journal: BMC structural biologysee more from them

Publication Website: http://www.biomedcentral.com/bmcstructbiol/

Issue Date: 2012

pages:14Identifiers

Urn: uuid:a9c8fa80-f938-49c4-b6ef-8ad449ef84d6

Source identifier: 340011

Eissn: 1472-6807

Doi: https://doi.org/10.1186/1472-6807-12-14

Issn: 1472-6807 Item Description

Type: Journal article;

Language: eng

Version: Publisher's versionKeywords: Humans Bacteria Metals Glutamyl Aminopeptidase Crystallography, X-Ray Catalytic Domain Protein Structure, Tertiary Substrate Specificity Multigene Family Amino Acid Sequence Molecular Sequence Data Biocatalysis Protein Multimerization Static Electricity Models, Molecular Tiny URL: pubs:340011

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Autor: Chaikuad, A - institutionUniversity of Oxford Oxford, MSD, Clinical Medicine, Structural Genomics Consortium - - - Pilka, ES - in

Fuente: https://ora.ox.ac.uk/objects/uuid:a9c8fa80-f938-49c4-b6ef-8ad449ef84d6



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