{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T03:43:31Z","timestamp":1772250211296,"version":"3.50.1"},"reference-count":33,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"5650","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Science"],"published-print":{"date-parts":[[2003,11,28]]},"abstract":"<jats:p>\n                    Unfolded proteins in the endoplasmic reticulum cause trans-autophosphorylation of the bifunctional transmembrane kinase Ire1, which induces its endoribonuclease activity. The endoribonuclease initiates nonconventional splicing of\n                    <jats:italic>HAC1<\/jats:italic>\n                    messenger RNAto trigger the unfolded-protein response (UPR). We explored the role of Ire1's kinase domain by sensitizing it through site-directed mutagenesis to the ATP-competitive inhibitor 1NM-PP1. Paradoxically, rather than being inhibited by 1NM-PP1, drug-sensitized Ire1 mutants required 1NM-PP1 as a cofactor for activation. In the presence of 1NM-PP1, drug-sensitized Ire1 bypassed mutations that inactivate its kinase activity and induced a full UPR. Thus, rather than through phosphorylation per se, a conformational change in the kinase domain triggered by occupancy of the active site with a ligand leads to activation of all known downstream functions.\n                  <\/jats:p>","DOI":"10.1126\/science.1090031","type":"journal-article","created":{"date-parts":[[2003,10,20]],"date-time":"2003-10-20T20:23:12Z","timestamp":1066681392000},"page":"1533-1537","source":"Crossref","is-referenced-by-count":207,"title":["Bypassing a Kinase Activity with an ATP-Competitive Drug"],"prefix":"10.1126","volume":"302","author":[{"given":"Feroz R.","family":"Papa","sequence":"first","affiliation":[{"name":"Department of Medicine, University of California, San Francisco, CA 94143\u20132200, USA."},{"name":"Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143\u20132200, USA."},{"name":"Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143\u20132200, USA."},{"name":"Howard Hughes Medical Institute, University of California, San Francisco, CA 94143\u20132200, USA."}]},{"given":"Chao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Francisco, CA 94143\u20132200, USA."},{"name":"Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143\u20132200, USA."},{"name":"Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143\u20132200, USA."},{"name":"Howard Hughes Medical Institute, University of California, San Francisco, CA 94143\u20132200, USA."}]},{"given":"Kevan","family":"Shokat","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Francisco, CA 94143\u20132200, USA."},{"name":"Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143\u20132200, USA."},{"name":"Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143\u20132200, USA."},{"name":"Howard Hughes Medical Institute, University of California, San Francisco, CA 94143\u20132200, USA."}]},{"given":"Peter","family":"Walter","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Francisco, CA 94143\u20132200, USA."},{"name":"Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143\u20132200, USA."},{"name":"Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143\u20132200, USA."},{"name":"Howard Hughes Medical Institute, University of California, San Francisco, CA 94143\u20132200, USA."}]}],"member":"221","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/355033a0"},{"key":"e_1_3_1_3_2","doi-asserted-by":"publisher","DOI":"10.1006\/scdb.1999.0315"},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0955-0674(00)00219-2"},{"key":"e_1_3_1_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90648-A"},{"key":"e_1_3_1_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81360-4"},{"key":"e_1_3_1_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00505-0"},{"key":"e_1_3_1_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80369-4"},{"key":"e_1_3_1_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81361-6"},{"key":"e_1_3_1_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1996.tb00666.x"},{"key":"e_1_3_1_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81469-5"},{"key":"e_1_3_1_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90521-Q"},{"key":"e_1_3_1_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.8.3565"},{"key":"e_1_3_1_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(98)70198-8"},{"key":"e_1_3_1_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/35036300"},{"key":"e_1_3_1_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/35030148"},{"key":"e_1_3_1_17_2","unstructured":"Single-letter abbreviations for the amino acid residues are as follows: A Ala; D Asp; G Gly; L Leu; and S Ser."},{"key":"e_1_3_1_18_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.211195798"},{"key":"e_1_3_1_19_2","unstructured":"F. R. Papa C. Zhang K. Shokat P. Walter data not shown."},{"key":"e_1_3_1_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00741-9"},{"key":"e_1_3_1_21_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.278.5338.680"},{"key":"e_1_3_1_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80835-1"},{"key":"e_1_3_1_23_2","unstructured":"Materials and methods are available as supporting material on Science Online."},{"key":"e_1_3_1_24_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.113.21.3697"},{"key":"e_1_3_1_25_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.20.11987"},{"key":"e_1_3_1_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)80357-3"},{"key":"e_1_3_1_27_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.4.2721"},{"key":"e_1_3_1_28_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.46.32803"},{"key":"e_1_3_1_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm829"},{"key":"e_1_3_1_30_2","doi-asserted-by":"publisher","DOI":"10.1017\/S1355838201002230"},{"key":"e_1_3_1_31_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/26.6.1522"},{"key":"e_1_3_1_32_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/27.2.439"},{"key":"e_1_3_1_33_2","doi-asserted-by":"publisher","DOI":"10.1002\/1521-1878(200101)23:1<69::AID-BIES1009>3.0.CO;2-K"},{"key":"e_1_3_1_34_2","unstructured":"We thank M. Stark for constructing the IRE1 C allele S. Ullrich for his initial effort in constructing Ire1 mutants and J. Kuriyan and members of the Walter and Shokat labs for valuable discussions. Supported by grants from the NIH to P.W. (GM32384) and K.S. (AI44009) and postdoctoral support from the UCSF Molecular Medicine Program (to F.P.). P.W. receives support as an investigator of the Howard Hughes Medical Institute."}],"container-title":["Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/science.1090031","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T21:33:25Z","timestamp":1704836005000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/science.1090031"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2003,11,28]]},"references-count":33,"journal-issue":{"issue":"5650","published-print":{"date-parts":[[2003,11,28]]}},"alternative-id":["10.1126\/science.1090031"],"URL":"https:\/\/doi.org\/10.1126\/science.1090031","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1016650.201171","asserted-by":"object"},{"id-type":"doi","id":"10.3410\/f.1016650.201241","asserted-by":"object"},{"id-type":"doi","id":"10.3410\/f.1016650.201383","asserted-by":"object"},{"id-type":"doi","id":"10.3410\/f.1016650.211435","asserted-by":"object"}]},"ISSN":["0036-8075","1095-9203"],"issn-type":[{"value":"0036-8075","type":"print"},{"value":"1095-9203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2003,11,28]]}}}