Fig. 1. PI3Kα: sequence and structure. (a) The sequence of PI3Kα. PI3Kα is a dimer comprised of p110α catalytic and p85α regulatory subunits. The p110α subunit contains five domains, i.e., adaptor-binding domain (ABD, residues 16–105, cyan), Ras binding domain (RBD, residues 187–289, yellow), C2 (residues 330–487, orange), helical (residues 517–694, green), and N-lobe (light purple) and C-lobe (dark purple) of the kinase (residues 695–1068) domain. The p85α subunit consists of the SH3 (residues 3–79), breakpoint-cluster region homology (BH, residues 113–301), nSH2 (residues 333–428), iSH2 (residues 431–598), and cSH2 (residues 624–718) domains. (b) The inactive PI3Kα conformation. The SH3, BH and cSH2 domains lack strong interactions with p110α, thus are missing in the structure. The inhibitory nSH2 domain interacts with C2, helical domain and kinase domain in p110α. (c) The interaction energies of nSH2 domain with C2, helical and kinase domains in p110α. The interaction energies are calculated by the sum of non-bonded van der Waals (vdW) and electrostatic interactions. The vdW and the electrostatic interactions are described by the potential energy function in the CHARMM 36 force field. (d) The membrane binding surface in the kinase domain cannot access the membrane because of steric clash of iSH2 domain. The membrane binding surface in the kinase domain is defined by the positions of _kinaseGlu⁷²⁶, _kinaseHis¹⁰⁴⁷ and _kinaseLys⁹⁴².