{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T15:14:54Z","timestamp":1772118894328,"version":"3.50.1"},"reference-count":52,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2024,12,30]],"date-time":"2024-12-30T00:00:00Z","timestamp":1735516800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003121","name":"Ferdowsi University of Mashhad","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003121","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Proteins"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The pathogenic G361A variant of CRAF, associated with increased intrinsic kinase activity in Noonan syndrome (NS), remains poorly understood in terms of its molecular and structural impact on kinase activity. To elucidate the mechanistic implications of the glycine to alanine substitution at residue 361 in CRAF, we employed molecular dynamics simulations. Our findings reveal that this mutation predominantly affects the ATP binding pocket and critical intermolecular interactions within the active cleft that favors the phosphate transfer reaction. Notably, our data highlight significant alterations in key interactions involving Lys470\/Asp486 and ATP.Mg\n                    <jats:sup>2+<\/jats:sup>\n                    in CRAF\n                    <jats:sup>G361A<\/jats:sup>\n                    that are absent in wild\u2010type CRAF. Additionally, we identified a novel interaction mode between Lys431 and \u03b3\u2010phosphate in wild\u2010type CRAF, a residue evolutionarily conserved in CRAFs but not in related kinases such as BRAF, ARAF, and KSR1\/2. Furthermore, observed shifts in the \u03b1C\u2010helix and G\u2010loop relative to the wild\u2010type correlate with an enlarged ATP\u2010binding cavity in the mutant, reflecting structural adaptations due to these mutations. Overall, these structural insights underscore the elevated intrinsic kinase activity of the CRAF\n                    <jats:sup>G361A<\/jats:sup>\n                    variant and provide crucial mechanistic details that could inform the development of specific inhibitors targeting this variant.\n                  <\/jats:p>","DOI":"10.1002\/prot.26769","type":"journal-article","created":{"date-parts":[[2024,12,30]],"date-time":"2024-12-30T04:25:58Z","timestamp":1735532758000},"page":"1022-1034","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Structural Insights Into the Impact of the Glycine\u2010Rich Loop Mutation in Noonan Syndrome on the\n                    <scp>ATP<\/scp>\n                    Binding Pocket of\n                    <scp>CRAF<\/scp>\n                    Kinase"],"prefix":"10.1002","volume":"93","author":[{"given":"Fatemeh","family":"Janati\u2010Fard","sequence":"first","affiliation":[{"name":"Stem Cell Biology, and Regenerative Medicine Research Group, Institute of Biotechnology Ferdowsi University of Mashhad  Mashhad Iran"},{"name":"Department of Chemistry, Faculty of Science Ferdowsi University of Mashhad  Mashhad Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5428-2512","authenticated-orcid":false,"given":"Mohammad R.","family":"Housaindokht","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science Ferdowsi University of Mashhad  Mashhad Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fatemeh","family":"Moosavi","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science Ferdowsi University of Mashhad  Mashhad Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8966-8960","authenticated-orcid":false,"given":"Saeideh","family":"Nakhaei\u2010Rad","sequence":"additional","affiliation":[{"name":"Stem Cell Biology, and Regenerative Medicine Research Group, Institute of Biotechnology Ferdowsi University of Mashhad  Mashhad Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,12,30]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1042\/BST20170528"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21422-x"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2024.168483"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2024.06.028"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-024-05959-3"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2963"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-023-05013-8"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1080\/07391102.2023.2187221"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng2073"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng2078"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-023-00650-x"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006684"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3420"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddz108"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.38569"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01636-09"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.5b01421"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0607656103"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1257"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-4089"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08833"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx349"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.21287"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.23354"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20945"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.5b00935"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/comjnl\/6.2.163"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/0010-4655(95)00042-E"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.540130805"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.464397"},{"key":"e_1_2_10_33_1","volume-title":"The PyMOL Molecular Graphics System, 2002","author":"Delano W. L.","year":"2002"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/3240674"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1039\/C5CP03136B"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.17505"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1186\/1758-2946-5-39"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.21334"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2016.03.021"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2016.12.003"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1039\/C7CP05038K"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M407586200"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1039\/D1SC03444H"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.csbj.2021.06.007"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-018-0171-x"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.75.3780"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1177\/1535370220959657"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-0657"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature00766"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.genrep.2020.100885"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1124642"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1186\/1479\u20105876\u201013\u2010S1\u2010P3.eCollection"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-03-3591"}],"container-title":["Proteins: Structure, Function, and Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/prot.26769","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,5]],"date-time":"2025-04-05T03:37:50Z","timestamp":1743824270000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/prot.26769"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,30]]},"references-count":52,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2025,5]]}},"alternative-id":["10.1002\/prot.26769"],"URL":"https:\/\/doi.org\/10.1002\/prot.26769","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1002\/PROT.26769\/v2\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/PROT.26769\/v2\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/PROT.26769\/v1\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/PROT.26769\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/PROT.26769\/v1\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/PROT.26769\/v2\/review1","asserted-by":"object"}]},"ISSN":["0887-3585","1097-0134"],"issn-type":[{"value":"0887-3585","type":"print"},{"value":"1097-0134","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,30]]},"assertion":[{"value":"2024-08-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}