Protein kinase B Pleckstrin Homology domain (Akt PH domain)

The Pleckstrin Homology (PH) domain of Protein kinase B (Akt) is a critical regulatory module that mediates the recruitment of the kinase to the plasma membrane (UniProt P31749). This recruitment occurs through high-affinity binding to phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and phosphatidylinositol (3,4)-bisphosphate (PI(3,4)P2), which are generated by Phosphoinositide 3-kinase (PI3K) (PubMed: 22510885). Once localized to the membrane, Akt undergoes conformational changes that allow for its phosphorylation by PDK1 and mTORC2, leading to full activation. Dysregulation of this process, often due to PTEN loss or PI3K mutations, leads to constitutive Akt signaling, a hallmark of many cancers and overgrowth syndromes like Proteus syndrome (PubMed: 21760564). Consequently, the PH domain has emerged as a significant therapeutic target for allosteric inhibitors that prevent membrane translocation or lock the kinase in an inactive conformation. Such inhibitors, including perifosine and miransertib, offer a more selective approach compared to traditional ATP-competitive inhibitors by targeting the unique PH-kinase interface (PubMed: 28137923). However, targeting Akt poses challenges such as systemic hyperglycemia due to the protein's essential role in insulin-mediated glucose uptake (PubMed: 21491404).

Other names

PKB PH domainPleckstrin homology domain of Protein Kinase BAkt PH domainRAC-alpha serine/threonine-protein kinase PH domain

Allosteric inhibition by binding to the PH domain, preventing membrane translocation, and stabilizing the inactive conformation.