The Structure of PI3K: Difference between revisions

The <scene name='User:David_Canner/Sandbox_P/Helical_overview/2'>helical domain in p110</scene>, whose function isn’t thoroughly understood, interacts with nSH2 via charge interactions. The HD residue, <scene name='User:David_Canner/Sandbox_P/Helical_domain/1'>Glu 542 forms a slat bridge with Arg 358 on NSH2 while Glu 545 interacts with NSH2 Lys 379</scene>. These residues are known hotspot mutations which are associated with various types of cancer. <ref name="Amzel"/> This loop in <scene name='User:David_Canner/Sandbox_P/Nsh2__and_helical_ligand_out/2'>the helical domain </scene> which contains the hotspots (residues 542-546) is located precisely where <scene name='User:David_Canner/Sandbox_P/Nsh2_ligand_just_ligand_full/1'> the phosphopeptide of NSH2 ligands, like PDGFR, bind to NSH2.</scene> The salt bridge formed between <scene name='User:David_Canner/Sandbox_P/Nsh2_disruption_of_salt/1'>Glu 542 and nSH2 is disrupted upon binding phosphorylated peptides</scene> like PDGFR, eliminating nSH2-mediated inhibition of p110α and activating the enzyme to phosphorylate PIP2 into PIP3. The hotspot mutation at Glu 542 accomplishes the same thing by eliminating the salt bridge and uninhibiting p110α. It is the <scene name='User:David_Canner/Sandbox_P/Kinase_with_atp_full/2'>kinase domain </scene> which <scene name='User:David_Canner/Sandbox_P/Kinase_with_atp_zoomed/3'>binds ATP to provide the phosphate group</scene> used to convert PIP2 into PIP3. <ref name="Amzel"/>