4AW1: Human PDK1 Kinase Domain in Complex with Allosteric Compound PS210 Bound to the PIF-Pocket

Citation:
Abstract
The PIF-pocket of AGC protein kinases participates in the physiologic mechanism of regulation by acting as a docking site for substrates and as a switch for the transduction of the conformational changes needed for activation or inhibition. We describe the effects of compounds that bind to the PIF-pocket of PDK1. In vitro, PS210 is a potent activator of PDK1, and the crystal structure of the PDK1-ATP-PS210 complex shows that PS210 stimulates the closure of the kinase domain. However, in cells, the prodrug of PS210 (PS423) acts as a substrate-selective inhibitor of PDK1, inhibiting the phosphorylation and activation of S6K, which requires docking to the PIF-pocket, but not affecting PKB/Akt. This work describes a tool to study the dynamics of PDK1 activity and a potential approach for drug discovery.
PDB ID: 4AW1Download
MMDB ID: 103498
PDB Deposition Date: 2012/5/30
Updated in MMDB: 2012/10
Experimental Method:
x-ray diffraction
Resolution: 1.68  Å
Source Organism:
Similar Structures:
Biological Unit for 4AW1: monomeric; determined by software (PISA)
Molecular Components in 4AW1
Label Count Molecule
Protein (1 molecule)
1
3-phosphoinositide-dependent Protein Kinase 1(Gene symbol: PDPK1)
Molecule annotation
Chemicals (10 molecules)
1
1
2
1
3
2
4
1
5
2
6
3
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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