{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T13:31:09Z","timestamp":1788269469363,"version":"build-2803163510"},"reference-count":67,"publisher":"Wiley","issue":"21","license":[{"start":{"date-parts":[[2022,6,16]],"date-time":"2022-06-16T00:00:00Z","timestamp":1655337600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/M026647\/1"],"award-info":[{"award-number":["MR\/M026647\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["13082029517"],"award-info":[{"award-number":["13082029517"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:sec>\n                    <jats:label\/>\n                    <jats:p>Human angiotensin I\u2010converting enzyme (ACE) has two isoforms, somatic ACE (sACE) and testis ACE (tACE). The functions of sACE are widespread, with its involvement in blood pressure regulation most extensively studied. sACE is composed of an N\u2010domain (nACE) and a C\u2010domain (cACE), both catalytically active but have significant structural differences, resulting in different substrate specificities. Even though ACE inhibitors are used clinically, they need much improvement because of serious side effects seen in patients (~\u200925\u201330%) with long\u2010term treatment due to nonselective inhibition of nACE and cACE. Investigation into the distinguishing structural features of each domain is therefore of vital importance for the development of domain\u2010specific inhibitors with minimal side effects. Here, we report kinetic data and high\u2010resolution crystal structures of both nACE (1.75\u2009\u00c5) and cACE (1.85\u2009\u00c5) in complex with fosinoprilat, a clinically used inhibitor. These structures allowed detailed analysis of the molecular features conferring domain selectivity by fosinoprilat. Particularly, altered hydrophobic interactions were observed to be a contributing factor. These experimental data contribute to improved understanding of the structural features that dictate ACE inhibitor domain selectivity, allowing further progress towards designing novel 2nd\u2010generation domain\u2010specific potent ACE inhibitors suitable for clinical administration, with a variety of potential future therapeutic benefits.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Database<\/jats:title>\n                    <jats:p>\n                      The atomic coordinates and structure factors for nACE\u2010fosinoprilat and cACE\u2010fosinoprilat structures have been deposited with codes\u2009\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/doi.org\/10.2210\/pdb7Z6Z\/pdb\">7Z6Z<\/jats:ext-link>\n                      and\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/doi.org\/10.2210\/pdb7Z70\/pdb\">7Z70<\/jats:ext-link>\n                      , respectively, in the RCSB Protein Data Bank,\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.pdb.org\">www.pdb.org<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/febs.16543","type":"journal-article","created":{"date-parts":[[2022,6,2]],"date-time":"2022-06-02T14:01:13Z","timestamp":1654178473000},"page":"6659-6671","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Structural basis for the inhibition of human angiotensin\u20101 converting enzyme by fosinoprilat"],"prefix":"10.1111","volume":"289","author":[{"given":"Gyles E.","family":"Cozier","sequence":"first","affiliation":[{"name":"Department of Biology and Biochemistry University of Bath  UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma C.","family":"Newby","sequence":"additional","affiliation":[{"name":"Department of Biology and Biochemistry University of Bath  UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylva L. U.","family":"Schwager","sequence":"additional","affiliation":[{"name":"Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine University of Cape Town  South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. Elwyn","family":"Isaac","sequence":"additional","affiliation":[{"name":"School of Biology University of Leeds  UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward D.","family":"Sturrock","sequence":"additional","affiliation":[{"name":"Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine University of Cape Town  South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3009-4058","authenticated-orcid":false,"given":"K. 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