4A07

Human PDK1 Kinase Domain in Complex with Allosteric Activator PS171 Bound to the PIF-Pocket

Summary for 4A07

• Entry DOI: 10.2210/pdb4a07/pdb
• Related: 1H1W 1OKY 1OKZ 1UU3 1UU7 1UU8 1UU9 1UVR 1W1D 1W1G 1W1H 1Z5M 2BIY 2VKI 2XCH 2XCK 4A06
• Descriptor: 3-PHOSPHOINOSITIDE-DEPENDENT PROTEIN KINASE 1, ADENOSINE-5'-TRIPHOSPHATE, (3S)-3-(4-CHLOROPHENYL)-4-(5,7-DICHLORO-1H-BENZIMIDAZOL-2-YL)BUTANOIC ACID, ... (6 entities in total)
• Functional Keywords: transferase, allosteric site
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm: O15530
• Total number of polymer chains: 1
• Total formula weight: 36900.69

Authors

Schulze, J.O.,Lopez-Garcia, L.A.,Froehner, W.,Zhang, H.,Navratil, J.,Hindie, V.,Zeuzem, S.,Alzari, P.M.,Neimanis, S.,Engel, M.,Biondi, R.M. (deposition date: 2011-09-08, release date: 2011-12-07, Last modification date: 2024-11-13)

Primary citation

Lopez-Garcia, L.A.,Schulze, J.O.,Frohner, W.,Zhang, H.,Suss, E.,Weber, N.,Navratil, J.,Amon, S.,Hindie, V.,Zeuzem, S.,Jorgensen, T.J.,Alzari, P.M.,Neimanis, S.,Engel, M.,Biondi, R.M.
Allosteric Regulation of Protein Kinase Pkczeta by the N-Terminal C1 Domain and Small Compounds to the Pif-Pocket.
Chem.Biol., 18:1463-, 2011

PubMed Abstract: Protein kinases are key mediators of cellular signaling, and therefore, their activities are tightly controlled. AGC kinases are regulated by phosphorylation and by N- and C-terminal regions. Here, we studied the molecular mechanism of inhibition of atypical PKCζ and found that the inhibition by the N-terminal region cannot be explained by a simple pseudosubstrate inhibitory mechanism. Notably, we found that the C1 domain allosterically inhibits PKCζ activity and verified an allosteric communication between the PIF-pocket of atypical PKCs and the binding site of the C1 domain. Finally, we developed low-molecular-weight compounds that bind to the PIF-pocket and allosterically inhibit PKCζ activity. This work establishes a central role for the PIF-pocket on the regulation of PKCζ and allows us to envisage development of drugs targeting the PIF-pocket that can either activate or inhibit AGC kinases.

PubMed: 22118680
DOI: 10.1016/J.CHEMBIOL.2011.08.010

Experimental method

X-RAY DIFFRACTION (1.85 Å)