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Many human cancers involve up-regulation of the phosphoinositide 3-kinase PI3Kα, with oncogenic mutations identified in both the p110α catalytic and the p85α regulatory subunits. We used crystallographic and biochemical approaches to gain insight into activating mutations in two noncatalytic p110α domains—the adaptor-binding and the helical domains. A structure of the adaptor-binding domain of p110α in a complex with the p85α inter–Src homology 2 (inter-SH2) domain shows that oncogenic mutations in the adaptor-binding domain are not at the inter-SH2 interface but in a polar surface patch that is a plausible docking site for other domains in the holo p110/p85 complex. We also examined helical domain mutations and found that the Glu545 to Lys545 (E545K) oncogenic mutant disrupts an inhibitory charge-charge interaction with the p85 N-terminal SH2 domain. These studies extend our understanding of the architecture of PI3Ks and provide insight into how two classes of mutations that cause a gain in function can lead to cancer.