4KS8

PAK6 kinase domain in complex with sunitinib

Summary for 4KS8

• Entry DOI: 10.2210/pdb4ks8/pdb
• Related: 4KS7
• Descriptor: Serine/threonine-protein kinase PAK 6, N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carbo xamide (3 entities in total)
• Functional Keywords: protein kinase, phosphotransfer, phosphorylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q9NQU5
• Total number of polymer chains: 1
• Total formula weight: 33700.03

Authors

Gao, J.,Boggon, T.J. (deposition date: 2013-05-17, release date: 2013-09-11, Last modification date: 2024-10-09)

Primary citation

Gao, J.,Ha, B.H.,Lou, H.J.,Morse, E.M.,Zhang, R.,Calderwood, D.A.,Turk, B.E.,Boggon, T.J.
Substrate and Inhibitor Specificity of the Type II p21-Activated Kinase, PAK6.
Plos One, 8:e77818-e77818, 2013

PubMed Abstract: The p21-activated kinases (PAKs) are important effectors of Rho-family small GTPases. The PAK family consists of two groups, type I and type II, which have different modes of regulation and signaling. PAK6, a type II PAK, influences behavior and locomotor function in mice and has an ascribed role in androgen receptor signaling. Here we show that PAK6 has a peptide substrate specificity very similar to the other type II PAKs, PAK4 and PAK5 (PAK7). We find that PAK6 catalytic activity is inhibited by a peptide corresponding to its N-terminal pseudosubstrate. Introduction of a melanoma-associated mutation, P52L, into this peptide reduces pseudosubstrate autoinhibition of PAK6, and increases phosphorylation of its substrate PACSIN1 (Syndapin I) in cells. Finally we determine two co-crystal structures of PAK6 catalytic domain in complex with ATP-competitive inhibitors. We determined the 1.4 Å co-crystal structure of PAK6 with the type II PAK inhibitor PF-3758309, and the 1.95 Å co-crystal structure of PAK6 with sunitinib. These findings provide new insights into the structure-function relationships of PAK6 and may facilitate development of PAK6 targeted therapies.

PubMed: 24204982
DOI: 10.1371/journal.pone.0077818

Experimental method

X-RAY DIFFRACTION (1.95 Å)