PDB 1Z5M deposited: 2005-03-18 modified: 2011-07-13
Title Crystal Structure Of N1-[3-[[5-bromo-2-[[3-[(1-pyrrolidinylcarbonyl)amino]phenyl]amino]-4-pyrimidinyl]amino]propyl]-2,2-dimethylpropanediamide Complexed with Human PDK1
Authors Adler, M., Alicke, B., Arnaiz, D.O., Biroc, S.L., Bryant, J., Buckman, B.O., Chang, Z., Dinter, H., Feldman, R.I., Ferrer, M., Finster, S., Kochanny, M.J., Lentz, D., Polokoff, M.A., Whitlow, M., Wu, J.M., Yuan, S., Zhu, D.
Structure factors resolution 2.17 rfactor 0.212 rfree 0.269
DPI 0.64 theoretical min: 0.26
Related PDB Entries 1H1W

The phosphoinositide 3-kinase/3-phosphoinositide-dependent kinase 1 (PDK1)/Akt signaling pathway plays a key role in cancer cell growth, survival, and tumor angiogenesis and represents a promising target for anticancer drugs. Here, we describe three potent PDK1 inhibitors, BX-795, BX-912, and BX-320 (IC(50) = 11-30 nm) and their initial biological characterization. The inhibitors blocked PDK1/Akt signaling in tumor cells and inhibited the anchorage-dependent growth of a variety of tumor cell lines in culture or induced apoptosis. A number of cancer cell lines with elevated Akt activity were >30-fold more sensitive to growth inhibition by PDK1 inhibitors in soft agar than on tissue culture plastic, consistent with the cell survival function of the PDK1/Akt signaling pathway, which is particularly important for unattached cells. BX-320 inhibited the growth of LOX melanoma tumors in the lungs of nude mice after injection of tumor cells into the tail vein. The effect of BX-320 on cancer cell growth in vitro and in vivo indicates that PDK1 inhibitors may have clinical utility as anticancer agents.

J.Biol.Chem. 2005 May; 280(20):19867-19874 doi:10.1074/jbc.M501367200

"3-phosphoinositide dependent protein kinase-1 (PDK1) plays a key role in regulating signalling pathways by activating AGC kinases such as PKB/Akt and S6K. Here we describe the 2.0 A crystal structure of the PDK1 kinase domain in complex with ATP. The structure defines the hydrophobic pocket termed the ""PIF-pocket"", which plays a key role in mediating the interaction and phosphorylation of certain substrates such as S6K1. Phosphorylation of S6K1 at its C-terminal PIF-pocket-interacting motif promotes the binding of S6K1 with PDK1. In the PDK1 structure, this pocket is occupied by a crystallographic contact with another molecule of PDK1. Interestingly, close to the PIF-pocket in PDK1, there is an ordered sulfate ion, interacting tightly with four surrounding side chains. The roles of these residues were investigated through a combination of site-directed mutagenesis and kinetic studies, the results of which confirm that this region of PDK1 represents a phosphate-dependent docking site. We discuss the possibility that an analogous phosphate-binding regulatory motif may participate in the activation of other AGC kinases. Furthermore, the structure of PDK1 provides a scaffold for the design of specific PDK1 inhibitors."

Embo J. 2002 Aug; 21(16):4219- doi:10.1093/EMBOJ/CDF437

Cross References
Database source Identifier Description
PubMed 15772071 JBCHA3
PubMed 12169624 EMJODG
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
1Z5M/0 1Z5M 0 monomer 0 1 6 2136