4HZR

Crystal structure of Ack1 kinase domain

Summary for 4HZR

• Entry DOI: 10.2210/pdb4hzr/pdb
• Related: 4HZS
• Descriptor: Activated CDC42 kinase 1, SULFATE ION, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: active state, phosphotransfer, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane: Q07912
• Total number of polymer chains: 2
• Total formula weight: 63520.57

Authors

Gajiwala, K.S. (deposition date: 2012-11-15, release date: 2013-02-06, Last modification date: 2024-02-28)

Primary citation

Gajiwala, K.S.,Maegley, K.,Ferre, R.,He, Y.A.,Yu, X.
Ack1: activation and regulation by allostery.
Plos One, 8:e53994-e53994, 2013

PubMed Abstract: The non-receptor tyrosine kinase Ack1 belongs to a unique multi-domain protein kinase family, Ack. Ack is the only family of SH3 domain containing kinases to have an SH3 domain following the kinase domain; others have their SH3 domains preceding the kinase domain. Previous reports have suggested that Ack1 does not require phosphorylation for activation and the enzyme activity of the isolated kinase domain is low relative to other kinases. It has been shown to dimerize in the cellular environment, which augments its enzyme activity. The molecular mechanism of activation, however, remains unknown. Here we present structural and biochemical data on Ack1 kinase domain, and kinase domain+SH3 domain that suggest that Ack1 in its monomeric state is autoinhibited, like EGFR and CDK. The activation of the kinase domain may require N-lobe mediated symmetric dimerization, which may be facilitated by the N-terminal SAM domain. Results presented here show that SH3 domain, unlike in Src family tyrosine kinases, does not directly control the activation state of the enzyme. Instead we speculate that the SH3 domain may play a regulatory role by facilitating binding of the MIG6 homologous region to the kinase domain. We postulate that features of Ack1 activation and regulation parallel those of receptor tyrosine kinase EGFR with some interesting differences.

PubMed: 23342057
DOI: 10.1371/journal.pone.0053994

Experimental method

X-RAY DIFFRACTION (1.31 Å)