4AW0

Human PDK1 Kinase Domain in Complex with Allosteric Compound PS182 Bound to the PIF-Pocket

Summary for 4AW0

• Entry DOI: 10.2210/pdb4aw0/pdb
• Related: 1H1W 1OKY 1OKZ 1UU3 1UU7 1UU8 1UU9 1UVR 1W1D 1W1G 1W1H 1Z5M 2BIY 2VKI 2XCH 2XCK 4A06 4A07 4AW1
• Descriptor: 3-PHOSPHOINOSITIDE-DEPENDENT PROTEIN KINASE 1, ADENOSINE-5'-TRIPHOSPHATE, [(1R)-3-(4-chlorophenyl)-3-oxo-1-phenylpropyl]propanedioic acid, ... (7 entities in total)
• Functional Keywords: transferase, allosteric regulation, allosteric site, phosphorylation, agc protein kinase
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm: O15530
• Total number of polymer chains: 1
• Total formula weight: 36601.61

Authors

Schulze, J.O.,Busschots, K.,Lopez-Garcia, L.A.,Lammi, C.,Stroba, A.,Zeuzem, S.,Piiper, A.,Alzari, P.M.,Neimanis, S.,Arencibia, J.M.,Engel, M.,Biondi, R.M. (deposition date: 2012-05-30, release date: 2012-10-03, Last modification date: 2024-11-13)

Primary citation

Busschots, K.,Lopez-Garcia, L.A.,Lammi, C.,Stroba, A.,Zeuzem, S.,Piiper, A.,Alzari, P.M.,Neimanis, S.,Arencibia, J.M.,Engel, M.,Schulze, J.O.,Biondi, R.M.
Substrate-Selective Inhibition of Protein Kinase Pdk1 by Small Compounds that Bind to the Pif-Pocket Allosteric Docking Site.
Chem.Biol., 19:1152-, 2012

PubMed 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.

PubMed: 22999883
DOI: 10.1016/J.CHEMBIOL.2012.07.017

Experimental method

X-RAY DIFFRACTION (1.43 Å)