The structural basis for Ras activation of PI3Kα lipid kinase.

ABSTRACT: PI3Kα is a principal Ras effector that phosphorylates PIP2 to PIP3 in the PI3K/Akt/mTOR pathway. How Ras activates PI3K has been unclear: is Ras' role confined to PI3K recruitment to the membrane or does Ras activation also involve allostery? Recently, we determined the mechanism of PI3Kα activation at the atomic level. We showed the vital role and significance of conformational change in PI3Kα activation. Here, by a 'best-match for hydrogen-bonding pair' (BMHP) computational protocol and molecular dynamics (MD) simulations, we model the atomic structure of KRas4B in complex with the Ras binding domain (RBD) of PI3Kα, striving to understand the mechanism of PI3Kα activation by Ras. Point mutations T208D, K210E, and K227E disrupt the KRas4B-RBD interface in the models, in line with the expe

SUBMITTER: Zhang M 

PROVIDER: S-EPMC6556208 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature