PDPK1

In biochemistry, PDK1 is a master kinase, which is crucial for the activation of AKT/PKB and many other AGC kinases including PKC, S6K, SGK. An important role for PDK1 is in the signalling pathways activated by several growth factors and hormones including insulin signalling. Mice lacking PDK1 die during early embryonic development, indicating that this enzyme is critical for transmiting the growth-promoting signals nescessary fro normal mammalian development. Mice that are deficient in PDK1 have a ~40% decrease in body mass, mild glucose intolerance, and are resitant to cancer brought about by hyperactivation of the PI3K pathway (PTEN+/-).

It is also known as "PDPK1" ("PDK" can be confused with pyruvate dehydrogenase kinase.)

Etymology
PDK1 stands for 3-phosphoinositide-dependent protein kinase 1. PDK1 functions downstream of PI3K through PDK1's interaction with membrane phospholipids including phosphatidylinositols, phosphatidylinositol (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate. PI3K indirectly regulates PDK1 by phosphorylating phosphatidylinositols which in turn generates phosphatidylinositol (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate. However, PDK1 is believed to be constitively active and does not always require phosphatidylinositols for its activities.

Phosphatidylinositols is only required for the activation at the membrane of some substrates including AKT. PDK1 however does not require membrane lipid binding for the efficient phosphorylation of most of its substrates in the cytosol (not at the cell membrane).

Structure
The structure of PDK1 can be divided into two domains; the kinase or catalytic domain and the PH domain. The PH domain functions mainly in the interaction of PDK1 with phosphatidylinositol (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate  which is important in localization and activation of some of membrane associated PDK1's substrates including AKT.

The kinase domain has three ligand binding sites; the substrate binding site, the ATP binding site, and the docking site (also known as PIF pocket). Several PDK1 substrates including AKT and Protein kinase C, require the binding at this docking site. Small molecule allosteric inhibitors of PDK1 were shown to selectively inhibit activation of substrates that require docking site interaction. However, these inhibitors do not bind to the active site and allow PDK1 to activate other substrates that do not require docking site interaction. PDK1 is constitively active and at present, there is no known inhibitor proteins for PDK1.

The activation of PDK1's main effector, AKT, is believed to require a proper orientation of the kinase and PH domains of PDK1 and AKT at the membrane.