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Originally published in Science Express on 16 October 2003
Science 28 November 2003:
Vol. 302. no. 5650, pp. 1533 - 1537
DOI: 10.1126/science.1090031
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Research Articles

Bypassing a Kinase Activity with an ATP-Competitive Drug

Feroz R. Papa,1,3* Chao Zhang,2 Kevan Shokat,2 Peter Walter3,4

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 HAC1 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.

1 Department of Medicine, University of California, San Francisco, CA 94143–2200, USA.
2 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143–2200, USA.
3 Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143–2200, USA.
4 Howard Hughes Medical Institute, University of California, San Francisco, CA 94143–2200, USA.

* To whom correspondence should be addressed. E-mail: frpapa{at}medicine.ucsf.edu

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