{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,26]],"date-time":"2025-10-26T15:07:22Z","timestamp":1761491242062,"version":"build-2065373602"},"reference-count":40,"publisher":"Wiley","issue":"S1","license":[{"start":{"date-parts":[[2021,6,29]],"date-time":"2021-06-29T00:00:00Z","timestamp":1624924800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000777","name":"University of Leeds","doi-asserted-by":"publisher","award":["P5","P3"],"award-info":[{"award-number":["P5","P3"]}],"id":[{"id":"10.13039\/501100000777","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Rapid Comm Mass Spectrometry"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>The protein kinase FGFR1 regulates cellular processes in human development. As over\u2010activity of FGFR1 is implicated with cancer, effective inhibitors are in demand. Type I inhibitors, which bind to the active form of FGFR1, are less effective than type II inhibitors, which bind to the inactive form. Screening to distinguish between type I and type II inhibitors is required.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>X\u2010ray crystallography was used to indicate whether a range of potential inhibitors bind to the active or inactive FGFR1 kinase conformation. The binding affinity of each ligand to FGFR1 was measured using biochemical methods. Electrospray ionisation \u2010 ion mobility spectrometry \u2010 mass spectrometry (ESI\u2010IMS\u2010MS) in conjunction with collision\u2010induced protein unfolding generated a conformational profile of each FGFR1\u2013ligand complex. The results indicate that the protein's conformational profile depends on whether the inhibitor is type I or type II.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>X\u2010ray crystallography confirmed which of the kinase inhibitors bind to the active or inactive form of FGFR1 kinase. Collision\u2010induced unfolding combined with ESI\u2010IMS\u2010MS showed distinct differences in the FGFR1 folding landscape for type I and type II inhibitors. Biochemical studies indicated a similar range of FGFR1 affinities for both types of inhibitors, thus providing confidence that the conformational variations detected using ESI\u2010IMS\u2010MS can be interpretated unequivocally and that this is an effective screening method.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>A robust ESI\u2010IMS\u2010MS method has been implemented to distinguish between the binding mode of type I and type II inhibitors by monitoring the conformational unfolding profile of FGFR1. This rapid method requires low sample concentrations and could be used as a high\u2010throughput screening technique for the characterisation of novel kinase inhibitors.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/rcm.9130","type":"journal-article","created":{"date-parts":[[2021,5,26]],"date-time":"2021-05-26T15:08:27Z","timestamp":1622041707000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Validation of ion mobility spectrometry \u2010 mass spectrometry as a screening tool to identify type II kinase inhibitors of FGFR1 kinase"],"prefix":"10.1002","volume":"39","author":[{"given":"Helen S.","family":"Beeston","sequence":"first","affiliation":[{"name":"Astbury Centre for Structural Molecular Biology &amp; Faculty of Biological Sciences University of Leeds  Leeds LS2 9JT UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tobias","family":"Klein","sequence":"additional","affiliation":[{"name":"Discovery Sciences, BioPharmaceuticals R&amp;D, AstraZeneca, Alderley Park  Macclesfield SK10 4TG UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7764-3931","authenticated-orcid":false,"given":"Richard A.","family":"Norman","sequence":"additional","affiliation":[{"name":"Discovery Sciences, BioPharmaceuticals R&amp;D, AstraZeneca, Alderley Park  Macclesfield SK10 4TG UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6119-676X","authenticated-orcid":false,"given":"Julie A.","family":"Tucker","sequence":"additional","affiliation":[{"name":"Discovery Sciences, BioPharmaceuticals R&amp;D, AstraZeneca, Alderley Park  Macclesfield SK10 4TG UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Malcolm","family":"Anderson","sequence":"additional","affiliation":[{"name":"Discovery Sciences, BioPharmaceuticals R&amp;D, AstraZeneca, Alderley Park  Macclesfield SK10 4TG UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1676-123X","authenticated-orcid":false,"given":"Alison E.","family":"Ashcroft","sequence":"additional","affiliation":[{"name":"Astbury Centre for Structural Molecular Biology &amp; Faculty of Biological Sciences University of Leeds  Leeds LS2 9JT UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geoffrey A.","family":"Holdgate","sequence":"additional","affiliation":[{"name":"Discovery Sciences, BioPharmaceuticals R&amp;D, AstraZeneca, Alderley Park  Macclesfield SK10 4TG UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,6,29]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-6-S4-S20"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2707"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.69.1.373"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio799"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0607656103"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-090308-173656"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.289.5486.1938"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1207759109"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsb770"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2007.010015"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm300126x"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2014.09.019"},{"issue":"11","key":"e_1_2_7_14_1","first-page":"4514","article-title":"High\u2010throughput tissue microarray analysis of 3p25 (RAF1) and 8p12 (FGFR1) copy number alterations in urinary bladder cancer","volume":"61","author":"Simon R","year":"2001","journal-title":"Cancer Res"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0020351"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3001451"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0022644"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/ac4012655"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0092-8674(00)80131-2"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.2210\/pdb4f63\/pdb"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-11-0312"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2011.01801.x"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444909047337"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1107\/S090744491003982X"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444911007773"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444910045749"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444906016076"},{"key":"e_1_2_7_29_1","unstructured":"BricogneG BlancE BrandlM Flensburg C. Keller P. Paciorek W. Roversi P. Sharff A. Smart O. Vonrhein C. &Womack T.2011.BUSTER V 2.11.2.http:\/\/wwwglobalphasingcom."},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444910007493"},{"volume-title":"The PyMOL Molecular Graphics System, version 1.2r3pre","author":"Pymol","key":"e_1_2_7_31_1"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-1443"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-05-0410"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja00067a054"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbapap.2012.11.013"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200702161"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jasms.2009.06.010"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr980139g"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm8010299"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0040144"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1214330110"}],"container-title":["Rapid Communications in Mass Spectrometry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/rcm.9130","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/rcm.9130","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/rcm.9130","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,26]],"date-time":"2025-10-26T10:31:41Z","timestamp":1761474701000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/rcm.9130"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,29]]},"references-count":40,"journal-issue":{"issue":"S1","published-print":{"date-parts":[[2025,5]]}},"alternative-id":["10.1002\/rcm.9130"],"URL":"https:\/\/doi.org\/10.1002\/rcm.9130","archive":["Portico"],"relation":{},"ISSN":["0951-4198","1097-0231"],"issn-type":[{"type":"print","value":"0951-4198"},{"type":"electronic","value":"1097-0231"}],"subject":[],"published":{"date-parts":[[2021,6,29]]},"assertion":[{"value":"2021-04-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-05-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-06-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e9130"}}