Crystal structures of the phosphorylated and unphosphorylated kinase domains of the Cdc42-associated tyrosine kinase ACK1

doi:10.1074/jbc.M406703200

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Papers In Press, published online ahead of print August 11, 2004
J. Biol. Chem, 10.1074/jbc.M406703200
Submitted on June 16, 2004
Revised on August 2, 2004
Accepted on August 11, 2004

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

Structural Biology, Exelixis, South San Francisco, CA 94083-0511

Corresponding Author: tstout{at}exelixis.com

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 structure 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 (AMP-PCP) 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.

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