{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T23:13:05Z","timestamp":1792710785394,"version":"4.5.0"},"reference-count":47,"publisher":"National Academy of Sciences","issue":"24","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2013,6,11]]},"abstract":"<jats:p>\n                    Multidrug resistance is a serious barrier to successful treatment of many human diseases, including cancer, wherein chemotherapeutics are exported from target cells by membrane-embedded pumps. The most prevalent of these pumps, the ATP-Binding Cassette transporter P-glycoprotein (P-gp), consists of two homologous halves each comprising one nucleotide-binding domain and six transmembrane helices. The transmembrane region encapsulates a hydrophobic cavity, accessed by portals in the membrane, that binds cytotoxic compounds as well as lipids and peptides. Here we use mass spectrometry (MS) to probe the intact P-gp small molecule-bound complex in a detergent micelle. Activation in the gas phase leads to formation of ions, largely devoid of detergent, yet retaining drug molecules as well as charged or zwitterionic lipids. Measuring the rates of lipid binding and calculating apparent\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>D<\/jats:italic>\n                    <\/jats:sub>\n                    values shows that up to six negatively charged diacylglycerides bind more favorably than zwitterionic lipids. Similar experiments confirm binding of cardiolipins and show that prior binding of the immunosuppressant and antifungal antibiotic cyclosporin A enhances subsequent binding of cardiolipin. Ion mobility MS reveals that P-gp exists in an equilibrium between different states, readily interconverted by ligand binding. Overall these MS results show how concerted small molecule binding leads to synergistic effects on binding affinities and conformations of a multidrug efflux pump.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1303888110","type":"journal-article","created":{"date-parts":[[2013,5,21]],"date-time":"2013-05-21T01:03:59Z","timestamp":1369098239000},"page":"9704-9709","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":169,"title":["Mass spectrometry reveals synergistic effects of nucleotides, lipids, and drugs binding to a multidrug resistance efflux pump"],"prefix":"10.1073","volume":"110","author":[{"given":"Julien","family":"Marcoux","sequence":"first","affiliation":[{"name":"Departments of aChemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheila C.","family":"Wang","sequence":"additional","affiliation":[{"name":"Departments of aChemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Argyris","family":"Politis","sequence":"additional","affiliation":[{"name":"Departments of aChemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eamonn","family":"Reading","sequence":"additional","affiliation":[{"name":"Departments of aChemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerome","family":"Ma","sequence":"additional","affiliation":[{"name":"Biochemistry, University of Oxford, Oxford OX1 3QZ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip C.","family":"Biggin","sequence":"additional","affiliation":[{"name":"Biochemistry, University of Oxford, Oxford OX1 3QZ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zhou","sequence":"additional","affiliation":[{"name":"Departments of aChemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Houchao","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinghai","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey","family":"Chang","sequence":"additional","affiliation":[{"name":"Skaggs School of Pharmacy and Pharmaceutical Sciences and Department of Pharmacology, School of Medicine, University of California at San Diego, La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Morgner","sequence":"additional","affiliation":[{"name":"Departments of aChemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol V.","family":"Robinson","sequence":"additional","affiliation":[{"name":"Departments of aChemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2013,5,20]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.2174\/138920011798357006"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1984"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj3330621"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1139\/o06-199"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-06-0155"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.20.10594"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1432-1327.2001.02041.x"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1168750"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.301192"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11448"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature05155"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0709388104"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1042\/bse0500161"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2007.06140.x"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2009.07.010"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2736(93)90339-2"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi301532c"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj3080381"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1159292"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0006137"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1210148"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-4157(00)00010-1"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi990064q"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi0024456"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20050047"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2012.40"},{"key":"e_1_3_3_27_2","first-page":"736","article-title":"Flipping and flopping\u2014Lipids on the move","volume":"63","author":"Sharom FJ","year":"2011","unstructured":"FJ Sharom, Flipping and flopping\u2014Lipids on the move. 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