1oky

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spinqualitylabelsall models 1oky, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

STRUCTURE OF HUMAN PDK1 KINASE DOMAIN IN COMPLEX WITH STAUROSPORINE

Overview

PDK1 (3-phosphoinositide-dependent protein kinase-1) is a member of the, AGC (cAMP-dependent, cGMP-dependent, protein kinase C) family of protein, kinases, and has a key role in insulin and growth-factor signalling, through phosphorylation and subsequent activation of a number of other AGC, kinase family members, such as protein kinase B. The staurosporine, derivative UCN-01 (7-hydroxystaurosporine) has been reported to be a, potent inhibitor for PDK1, and is currently undergoing clinical trials for, the treatment of cancer. Here, we report the crystal structures of, staurosporine and UCN-01 in complex with the kinase domain of PDK1. We, show that, although staurosporine and UCN-01 interact with the PDK1 active, site in an overall similar manner, the UCN-01 7-hydroxy group, which is, not present in staurosporine, generates direct and water-mediated hydrogen, bonds with active-site residues. Inhibition data from UCN-01 tested, against a panel of 29 different kinases show a different pattern of, inhibition compared with staurosporine. We discuss how these differences, in inhibition could be attributed to specific interactions with the, additional 7-hydroxy group, as well as the size of the, 7-hydroxy-group-binding pocket. This information could lead to, opportunities for structure-based optimization of PDK1 inhibitors.

About this Structure

1OKY is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as Transferred entry: 2.7.11.1, with EC number 2.7.1.37 Known structural/functional Site: . Full crystallographic information is available from OCA.

Reference

Structural basis for UCN-01 (7-hydroxystaurosporine) specificity and PDK1 (3-phosphoinositide-dependent protein kinase-1) inhibition., Komander D, Kular GS, Bain J, Elliott M, Alessi DR, Van Aalten DM, Biochem J. 2003 Oct 15;375(Pt 2):255-62. PMID:12892559

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