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Activating RAS mutations can be subclassified based on their activating mechanisms. Understanding the structural basis for these mechanisms may provide clues for how to manage associated health conditions. We determined high\u2010resolution X\u2010ray structures of the RASopathy mutant KRAS<jats:sup>P34R<\/jats:sup> seen in NS and CFCS. GTP and GDP\u2010bound KRAS<jats:sup>P34R<\/jats:sup> crystallized in multiple forms, with each lattice consisting of multiple protein conformations. In all GTP\u2010bound conformations, the switch regions are not compatible with GAP binding, suggesting a structural mechanism for the GAP insensitivity of this RAS mutant. However, GTP\u2010bound conformations are compatible with intrinsic nucleotide hydrolysis, including one that places R34 in a position analogous to the GAP arginine finger or intrinsic arginine finger found in heterotrimeric G proteins, which may support intrinsic GTP hydrolysis. We also note that the affinity between KRAS<jats:sup>P34R<\/jats:sup> and RAF\u2010RBD is decreased, suggesting another possible mechanism for dampening of RAS signaling. These results may provide a foothold for development of new mutation\u2010specific strategies to address KRAS<jats:sup>P34R<\/jats:sup>\u2010driven diseases.<\/jats:p>","DOI":"10.1002\/bdr2.1647","type":"journal-article","created":{"date-parts":[[2020,3,18]],"date-time":"2020-03-18T21:41:27Z","timestamp":1584567687000},"page":"708-717","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["GTP hydrolysis is modulated by Arg34 in the RASopathy\u2010associated KRAS<sup>P34R<\/sup>"],"prefix":"10.1002","volume":"112","author":[{"given":"Asim K.","family":"Bera","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Radiation Oncology The University of Texas Southwestern Medical Center at Dallas  Dallas Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Radiation Oncology The University of Texas Southwestern Medical Center at Dallas  Dallas Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunya","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Radiation Oncology The University of Texas Southwestern Medical Center at Dallas  Dallas Texas"},{"name":"Department of Respiratory Medicine The First Affiliated Hospital of Zhengzhou University  Zhengzhou Henan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lianbo","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Radiation Oncology The University of Texas Southwestern Medical Center at Dallas  Dallas Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sudershan","family":"Gondi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Radiation Oncology The University of Texas Southwestern Medical Center at Dallas  Dallas Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Radiation Oncology The University of Texas Southwestern Medical Center at Dallas  Dallas Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Nelson","sequence":"additional","affiliation":[{"name":"Brigham Young University  Provo Utah"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Goujun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine The First Affiliated Hospital of Zhengzhou University  Zhengzhou Henan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3653-5923","authenticated-orcid":false,"given":"Kenneth D.","family":"Westover","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Radiation Oncology The University of Texas Southwestern Medical Center at Dallas  Dallas Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,3,18]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444909052925"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsb0997-686"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA119.009131"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.05.018"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0912226107"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1694-1"},{"key":"e_1_2_9_8_1","volume-title":"The PyMOL molecular graphics system","author":"DeLano W. 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