9XW5

Cryo-EM structure of PI3Kalpha H1047R mutation in complex with STX-478

Summary for 9XW5

• Entry DOI: 10.2210/pdb9xw5/pdb
• EMDB information: 67325
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform, Phosphatidylinositol 3-kinase regulatory subunit alpha, N-(2-aminopyrimidin-5-yl)-N'-[(1R)-1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]urea (3 entities in total)
• Functional Keywords: phosphoinositide 3-kinase, drug target, ligand, binding pocket, hotspot mutation, allosteric inhbitor, structural protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 211866.12

Authors

Liu, X.,Chen, Y.,Li, G.,Chen, A.,Zhou, Q.,Wang, M.-W. (deposition date: 2025-11-27, release date: 2026-09-23, Last modification date: 2026-10-07)

Primary citation

Liu, X.,Chen, Y.,Li, G.,Chen, A.,Zhou, Q.,Wang, M.W.
Molecular architecture responsible for specific inhibition of oncogenic PI3K alpha mutants by RLY-2608 and STX-478.
Acta Pharm Sin B, 16:5884-5900, 2026

PubMed Abstract: Hotspot mutations in phosphoinositide 3-kinase alpha (PI3K), such as H1047R, E542K, and E545K, drive tumorigenesis across multiple cancer types. Orthosteric PI3K inhibitors are effective but have toxicity against wild-type PI3K, the emergence of resistance, and a narrow therapeutic index. Allosteric inhibitors such as RLY-2608 and STX-478 offer a promising path toward mutant-specific suppression, yet the structural basis for their selectivity and mechanisms of action remain elusive. Here, we report high-resolution cryogenic electron microscopy structures of RLY-2608- and STX-478-bound H1047R, E542K, and E545K, revealing a shared cryptic allosteric pocket, accessible only through a major conformational rearrangement of the activation loop that is stabilized in oncogenic mutants. While both inhibitors occupy this pocket, they have distinct interaction networks and propagate divergent allosteric activities: RLY-2608 induces large-scale remodeling of catalytic and membrane-interacting elements, whereas STX-478 reinforces autoinhibitory interfaces between p110 and p85 subunits. Comparative analysis provides structural insights into their differentiated potency and selectivity.

PubMed: 42764855
DOI: 10.1016/j.apsb.2026.07.003

Experimental method

ELECTRON MICROSCOPY (3.31 Å)