PIK3CA somatic mutations in breast cancer: Mechanistic insights from Langevin dynamics simulations

摘要: Somatic mutations in PIK3CA (phosphati-dylinositol-3 kinase, catalytic subunit, alpha isoform) are reported breast and other human cancers to concentrate at hotspots within its kinase helical domains. Most of these cause gain function vitro associated with oncogenicity vivo. However, little is known about the mechanisms driving tumor development. We have performed computational structural studies on a homology model wildtype plus recurrent H1047R, H1047L, P539R mutations, located domains, respectively. The time evolution structures show that H1047R/L mutants exhibit larger area cleft between N- C-lobes compared could facilitate entrance substrates. This might yield enhanced substrate-to-product turnover oncogenicity. In addition, display increased activation loop mobility, wildtype. mutant forms more hydrogen bonds salt-bridge interactions than wildtype, properties thermostability. Mutant-specific differences behavior suggest structure-based mutant-specific inhibitors can be designed for PIK3CA-positive cancers.