4O0R
Back pocket flexibility provides group-II PAK selectivity for type 1 kinase inhibitors
Summary for 4O0R
Entry DOI | 10.2210/pdb4o0r/pdb |
Related | 4O0T 4O0V 4O0X 4O0Y |
Descriptor | Serine/threonine-protein kinase PAK 1, PF-3758309 (3 entities in total) |
Functional Keywords | pak1, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
Biological source | Homo sapiens (human) |
Total number of polymer chains | 2 |
Total formula weight | 67579.63 |
Authors | |
Primary citation | Staben, S.T.,Feng, J.A.,Lyle, K.,Belvin, M.,Boggs, J.,Burch, J.D.,Chua, C.C.,Cui, H.,Dipasquale, A.G.,Friedman, L.S.,Heise, C.,Koeppen, H.,Kotey, A.,Mintzer, R.,Oh, A.,Roberts, D.A.,Rouge, L.,Rudolph, J.,Tam, C.,Wang, W.,Xiao, Y.,Young, A.,Zhang, Y.,Hoeflich, K.P. Back Pocket Flexibility Provides Group II p21-Activated Kinase (PAK) Selectivity for Type I 1/2 Kinase Inhibitors. J.Med.Chem., 57:1033-1045, 2014 Cited by PubMed Abstract: 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. PubMed: 24432870DOI: 10.1021/jm401768t PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
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