4O0Y: Back Pocket Flexibility Provides Group-ii Pak Selectivity For Type 1 Kinase Inhibitors

Structure-based methods were used to design a potent and highly selective group II p21-activated kinase (PAK) inhibitor with a novel binding mode, compound 17. Hydrophobic interactions within a lipophilic pocket past the methionine gatekeeper of group II PAKs approached by these type I 1/2 binders were found to be important for improving potency. A structure-based hypothesis and strategy for achieving selectivity over group I PAKs, and the broad kinome, based on unique flexibility of this lipophilic pocket, is presented. A concentration-dependent decrease in tumor cell migration and invasion in two triple-negative breast cancer cell lines was observed with compound 17.
PDB ID: 4O0YDownload
MMDB ID: 117543
PDB Deposition Date: 2013/12/14
Updated in MMDB: 2014/03
Experimental Method:
x-ray diffraction
Resolution: 2.2  Å
Source Organism:
Similar Structures:
Biological Unit for 4O0Y: monomeric; determined by author and by software (PISA)
Molecular Components in 4O0Y
Label Count Molecule
Protein (1 molecule)
Serine/threonine-protein Kinase PAK 4(Gene symbol: PAK4)
Molecule annotation
Chemical (1 molecule)
* Click molecule labels to explore molecular sequence information.

Citing MMDB