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Science 10 October 2008:
Vol. 322. no. 5899, pp. 265 - 268
DOI: 10.1126/science.1162403
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Reports

Small Molecule-Induced Allosteric Activation of the Vibrio cholerae RTX Cysteine Protease Domain

Patrick J. Lupardus,1* Aimee Shen,3* Matthew Bogyo,3{dagger} K. Christopher Garcia1,2{dagger}

Vibrio cholerae RTX (repeats in toxin) is an actin-disrupting toxin that is autoprocessed by an internal cysteine protease domain (CPD). The RTX CPD is efficiently activated by the eukaryote-specific small molecule inositol hexakisphosphate (InsP6), and we present the 2.1 angstrom structure of the RTX CPD in complex with InsP6. InsP6 binds to a conserved basic cleft that is distant from the protease active site. Biochemical and kinetic analyses of CPD mutants indicate that InsP6 binding induces an allosteric switch that leads to the autoprocessing and intracellular release of toxin-effector domains.

1 Department of Molecular and Cellular Physiology and Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
2 Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
3 Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: mbogyo{at}stanford.edu (M.B.); kcgarcia{at}stanford.edu (K.C.G.)

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