Structural insights into the inhibitory mechanism of angiotensin-I converting enzyme by the lactotripeptides IPP and VPP

Kyle S. Gregory, Gyles E. Cozier, Sylva L. U. Schwager, Edward D. Sturrock, K. Ravi Acharya

Research output: Contribution to journalArticlepeer-review

Abstract

Human somatic angiotensin-1-converting enzyme (sACE) is composed of a catalytic N-(nACE) and C-domain (cACE) of similar size with different substrate specificities. It is involved in the regulation of blood pressure by converting angiotensin I to the vasoconstrictor angiotensin II and has been a major focus in the development of therapeutics for hypertension. Bioactive peptides from various sources, including milk, have been identified as natural ACE inhibitors. We report the structural basis for the role of two lacototripeptides, Val-Pro-Pro and Ile-Pro-Pro, in domain-specific inhibition of ACE using X-ray crystallography and kinetic analysis. The lactotripeptides have preference for nACE due to altered polar interactions distal to the catalytic zinc ion. Elucidating the mechanism of binding and domain selectivity of these peptides also provides important insights into the functional roles of ACE.
Original languageEnglish
Pages (from-to)242-251
Number of pages10
JournalFEBS Letters
Volume598
Issue number2
Early online date30 Oct 2023
DOIs
Publication statusPublished - 31 Jan 2024

Bibliographical note

Research Funding:
Biotechnology and Biological Sciences Research Council. Grant Number: BB/X001032/1

National Research Foundation (South Africa). Grant Number: 13082029517

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