{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T14:51:52Z","timestamp":1772117512274,"version":"3.50.1"},"reference-count":56,"publisher":"Wiley","issue":"23","license":[{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["FEBS Letters"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:sec>\n                    <jats:label\/>\n                    <jats:p>\n                      Genetic variants of various cytochrome P450 (CYP) enzymes significantly impact pharmacokinetics. The highly polymorphic hepatic CYP2C9 metabolizes ~\u200915% of clinically used drugs. This study aimed to characterize the ligand\u2010binding properties of the understudied CYP2C9.57 variant (N204H mutation located in the active site) using spectrophotometric titration with diverse ligands. Type I ligands (diclofenac, tamoxifen) produced unusual reverse type II spectral responses (\u03bb\n                      <jats:sub>max<\/jats:sub>\n                      \u2009~\u2009410\u2009nm and \u03bb\n                      <jats:sub>min<\/jats:sub>\n                      430\u2013437\u2009nm), while diclofenac, cyproconazole, and fluconazole showed spectral transitions suggesting dual binding modes. Unlike the wild\u2010type protein, the N204H mutation significantly altered ligand binding behavior. A weak cooperative effect (with the Hill coefficients ranging from 0.93 to 2.08) was observed across compounds and isoforms. The N204H mutation in the F\/G region likely reduces active site cavity volume, with His204 forming additional contacts that appear to restrict ligand access to the heme iron. These findings provide insights for predicting altered drug metabolism, supporting personalized medicine.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:label\/>\n                    <jats:p>\n                      <jats:boxed-text content-type=\"box\" position=\"anchor\">\n                        <jats:caption>\n                          <jats:title>Impact statement<\/jats:title>\n                        <\/jats:caption>\n                        <jats:p>This study provides fundamental insights into the impact of genetic polymorphisms on CYP2C9 enzyme function, specifically the N204H mutation. By revealing alterations in ligand binding behavior and structural changes within the F\/G region, these findings contribute to a deeper understanding of pharmacokinetics and may aid future advancements in drug discovery.<\/jats:p>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/1873-3468.70159","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T08:30:33Z","timestamp":1757493033000},"page":"3501-3523","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cytochrome\n                    <scp>P<\/scp>\n                    450 F\u2010helix\n                    <scp>N<\/scp>\n                    204\n                    <scp>H<\/scp>\n                    mutation in\n                    <scp>CYP<\/scp>\n                    2\n                    <scp>C<\/scp>\n                    9.57 genetic variant reveals non\u2010typical ligand binding properties"],"prefix":"10.1002","volume":"599","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3432-0064","authenticated-orcid":false,"given":"Maryia","family":"Kisel","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Diagnostics and Biotechnology Institute of Bioorganic Chemistry of the National Academy of Sciences of Belarus  Minsk Belarus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michail","family":"Shapira","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Diagnostics and Biotechnology Institute of Bioorganic Chemistry of the National Academy of Sciences of Belarus  Minsk Belarus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrei","family":"Gilep","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Diagnostics and Biotechnology Institute of Bioorganic Chemistry of the National Academy of Sciences of Belarus  Minsk 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