Oncogenic PI3Kα variants reveal graded conformational spectrum with mutation-specific cryptic pockets

Area of Science:

• Molecular Biology
• Biochemistry
• Genetics

Background:

• Cancer-prone alleles often have single hotspot mutations.
• The 'one-two punch' hypothesis suggests combined mutations create diverse clinical phenotypes.
• Oncogenic PI3Kα variants are linked to tumors and developmental disorders.

Purpose of the Study:

• Investigate the impact of single and double mutations on PI3Kα conformation.
• Understand how these variants affect enzyme activity and substrate recruitment.
• Identify potential drug targets and therapeutic strategies for PI3Kα variants.

Main Methods:

• Atomistic molecular dynamics (MD) simulations were employed.
• Conformational profiles of wild-type, single-mutant, and double-mutant PI3Kα were analyzed.
• Mechanisms of PIP2 substrate recruitment and allosteric drug targeting were explored.

Main Results:

• Single and double PI3Kα mutations expand conformational profiles.
• Double mutations significantly shift ensembles towards the active form.
• Mutants facilitate nSH2 release, iSH2 shift, and A-loop protrusion, enhancing PIP2 recruitment.
• Cryptic pockets within PI3Kα were identified as potential drug targets.

Conclusions:

• PI3Kα variants exhibit diverse conformational states influenced by mutation load.
• A conformational selection strategy using allosteric drugs is proposed for graded variants.
• Targeting mutation-specific cryptic pockets offers a promising therapeutic avenue.