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J. Biol. Chem., Vol. 279, Issue 42, 44039-44045, October 15, 2004

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Crystal Structures of the Phosphorylated and Unphosphorylated Kinase Domains of the Cdc42-associated Tyrosine Kinase ACK1^*

Julie C. Lougheed, Rui-Hong Chen, Polly Mak, and Thomas J. Stout

From the Exelixis, Incorporated, South San Francisco, California 94083-0511

ACK1 is a multidomain non-receptor tyrosine kinase that is an effector of the Cdc42 GTPase. Members of the ACK family have a unique domain ordering and are the only tyrosine kinases known to interact with Cdc42. In contrast with many protein kinases, ACK1 has only a modest increase in activity upon phosphorylation. We have solved the crystal structures of the human ACK1 kinase domain in both the unphosphorylated and phosphorylated states. Comparison of these structures reveals that ACK1 adopts an activated conformation independent of phosphorylation. Furthermore, the unphosphorylated activation loop is structured, and its conformation resembles that seen in activated tyrosine kinases. In addition to the apo structure, complexes are also presented with a non-hydrolyzable nucleotide analog (adenosine 5'-(,-methylenetriphosphate)) and with the natural product debromohymenialdisine, a general inhibitor of many protein kinases. Analysis of these structures reveals a typical kinase fold, a pre-organization into the activated conformation, and an unusual substrate-binding cleft.

Received for publication, June 16, 2004 , and in revised form, August 2, 2004.

The atomic coordinates and structure factors (code 1U46, 1U54, and 1U4D) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* The facilities at the Advanced Light Source are supported by the United States Department of Energy and at the Stanford Synchrotron Radiation Laboratory are supported by the Office of Biological and Environmental Research, Department of Energy, and by the National Center for Research Resources, Biomedical Technology Program, and NIGMS, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Exelixis, Inc., 170 Harbor Way, P. O. Box 511, South San Francisco, CA 94083-0511. Tel.: 650-837-8129; Fax: 650-837-8181; E-mail: tstout{at}exelixis.com.

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