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A familial\n                    <jats:italic>PDE5A<\/jats:italic>\n                    variant resulting in an N\u2010terminal truncation (\u2206M1\u2010Q91) in PDE5A2 has been linked to premature ischemic heart disease, but its functional impact is unclear. Using computational analysis and BRET\u2010based biosensors, we show that \u2206M1\u2010Q91 deletion alters structural dynamics and reduces the efficacy of cGMP\u2010induced conformational change in PDE5. Molecular dynamics simulations and normal mode analysis using structural models revealed altered dynamics and correlated motions in the mutant. BRET assays showed a higher EC\n                    <jats:sub>50<\/jats:sub>\n                    for cGMP\u2010induced, but not sildenafil\u2010induced, conformational change in the \u2206M1\u2010Q91 mutant PDE5A2. These findings suggest that M1\u2010Q91 deletion impairs cGMP\u2010mediated allosteric regulation in PDE5A2 without altering inhibitor sensitivity, offering insights into potential precision therapies targeting this variant.\n                  <\/jats:p>","DOI":"10.1002\/1873-3468.70292","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T04:52:13Z","timestamp":1770094333000},"page":"1101-1113","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Ischemic heart disease\u2010associated \u2206\n                    <scp>M1<\/scp>\n                    \u2010\n                    <scp>Q91 PDE5A2<\/scp>\n                    mutant shows reduced efficacy for\n                    <scp>cGMP<\/scp>\n                    , but not sildenafil, binding\u2010induced conformational change"],"prefix":"10.1002","volume":"600","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3441-2631","authenticated-orcid":false,"given":"Wesam S.","family":"Ahmed","sequence":"first","affiliation":[{"name":"College of Health &amp; Life Sciences Hamad Bin Khalifa University  Doha Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7191-5109","authenticated-orcid":false,"given":"Asma","family":"Fatima","sequence":"additional","affiliation":[{"name":"College of Health &amp; Life Sciences Hamad Bin Khalifa University  Doha Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8932-9114","authenticated-orcid":false,"given":"Anupriya M.","family":"Geethakumari","sequence":"additional","affiliation":[{"name":"College of Health &amp; Life Sciences Hamad Bin Khalifa University  Doha Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9194-4127","authenticated-orcid":false,"given":"Kabir H.","family":"Biswas","sequence":"additional","affiliation":[{"name":"College of Health &amp; Life Sciences Hamad Bin Khalifa University  Doha Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,2,2]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2020.111128"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-022-00756-z"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmr.2025.100042"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ijir.3900802"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14205"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.58.3.5"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.56.1.124"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm030056e"},{"key":"e_1_2_9_10_1","unstructured":"WHO(2018)Noncommunicable diseases country profiles 2018."},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpubh.2024.1391836"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2023.11.007"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurjpc\/zwae281"},{"key":"e_1_2_9_14_1","unstructured":"ReynoldsHR(2021)Outcomes in the ISCHEMIA Trial Based on Coronary Artery Disease and Ischemia Severity."},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2020.11.010"},{"key":"e_1_2_9_16_1","first-page":"1241","article-title":"A decade of genome\u2010wide association studies for coronary artery disease: the challenges ahead","volume":"114","author":"Erdmann J","year":"2018","journal-title":"Cardiovasc Res"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacbts.2021.04.001"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/joim.13362"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3396"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10405"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2016.11.056"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3913"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.120.052975"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abj8754"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1914677117"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw1081"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2025.168996"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0021889892009944"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btz828"},{"key":"e_1_2_9_30_1","doi-asserted-by":"crossref","unstructured":"WohlwendJ CorsoG PassaroS GetzN ReveizM LeidalK SwiderskiW AtkinsonL PortnoiT ChinnIet\u00a0al. 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