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After glucose enters the cell, hexokinases convert it to glucose-6-phosphate (Glc-6P) for use in anaerobic fermentation, aerobic oxidative phosphorylation, and the pentose-phosphate pathway. We here describe a genetic screen in <jats:italic>Saccharomyces cerevisiae<\/jats:italic> that generated a novel spontaneous mutation in hexokinase-2, <jats:italic>hxk2<\/jats:italic><jats:sup>G238V<\/jats:sup>, that confers resistance to the toxic glucose analog 2-deoxyglucose (2DG). Wild-type hexokinases convert 2DG to 2-deoxyglucose-6-phosphate (2DG-6P), but 2DG-6P cannot support downstream glycolysis, resulting in a cellular starvation-like response. Curiously, though the <jats:italic>hxk2<\/jats:italic><jats:sup>G238V<\/jats:sup> mutation encodes a loss-of-function allele, the affected amino acid does not interact directly with bound glucose, 2DG, or ATP. Molecular dynamics simulations suggest that Hxk2<jats:sup>G238V<\/jats:sup> impedes sugar binding by altering the protein dynamics of the glucose-binding cleft, as well as the large-scale domain-closure motions required for catalysis. These findings shed new light on Hxk2 dynamics and highlight how allosteric changes can influence catalysis, providing new structural insights into this critical regulator of carbohydrate metabolism. Given that hexokinases are upregulated in some cancers and that 2DG and its derivatives have been studied in anti-cancer trials, the present work also provides insights that may apply to cancer biology and drug resistance.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1009929","type":"journal-article","created":{"date-parts":[[2022,3,2]],"date-time":"2022-03-02T18:59:13Z","timestamp":1646247553000},"page":"e1009929","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":18,"title":["Novel mutation in hexokinase 2 confers resistance to 2-deoxyglucose by altering protein dynamics"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5565-8614","authenticated-orcid":true,"given":"Erich","family":"Hellemann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1220-1574","authenticated-orcid":true,"given":"Jennifer L.","family":"Walker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7788-0005","authenticated-orcid":true,"given":"Mitchell A.","family":"Lesko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dakshayini G.","family":"Chandrashekarappa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin C.","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0966-288X","authenticated-orcid":true,"given":"Allyson F.","family":"O\u2019Donnell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5808-4097","authenticated-orcid":true,"given":"Jacob D.","family":"Durrant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,3,2]]},"reference":[{"issue":"2","key":"pcbi.1009929.ref001","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/BF00226892","article-title":"Mechanism of liver glucokinase","volume":"44","author":"D Pollard-Knight","year":"1982","journal-title":"Molecular and cellular biochemistry"},{"key":"pcbi.1009929.ref002","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1146\/annurev-cellbio-092910-154237","article-title":"Aerobic glycolysis: Meeting the metabolic requirements of cell proliferation","volume":"27","author":"SY Lunt","year":"2011","journal-title":"Annual review of cell and developmental biology"},{"issue":"16","key":"pcbi.1009929.ref003","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.2174\/0929867033457269","article-title":"Hexokinase II: The integration of energy metabolism and control of apoptosis","volume":"10","author":"JG Pastorino","year":"2003","journal-title":"Current medicinal chemistry"},{"key":"pcbi.1009929.ref004","volume-title":"Hexokinase-2 bound to mitochondria: Cancer\u2019s stygian link to the \u201cwarburg effect\u201d and a pivotal target for effective therapy","author":"SP Mathupala"},{"issue":"3","key":"pcbi.1009929.ref005","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.radonc.2009.06.025","article-title":"Pyruvate into lactate and back: From the warburg effect to symbiotic energy fuel exchange in cancer cells","volume":"92","author":"O. 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