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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\u2010Pro\u2010Pro and Ile\u2010Pro\u2010Pro, in domain\u2010specific inhibition of ACE using X\u2010ray 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.<\/jats:p>","DOI":"10.1002\/1873-3468.14768","type":"journal-article","created":{"date-parts":[[2023,10,31]],"date-time":"2023-10-31T00:57:47Z","timestamp":1698713867000},"page":"242-251","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Structural insights into the inhibitory mechanism of angiotensin\u2010I\u2010converting enzyme by the lactotripeptides IPP and VPP"],"prefix":"10.1002","volume":"598","author":[{"given":"Kyle S.","family":"Gregory","sequence":"first","affiliation":[{"name":"Department of Life Sciences University of Bath  UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gyles E.","family":"Cozier","sequence":"additional","affiliation":[{"name":"Department of Life Sciences University of Bath  UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylva L. 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