9CML

Crystal structure of p110alpha-RAS binding domain (RBD) in complex with molecular glue D223

This is a non-PDB format compatible entry.

Summary for 9CML

• Entry DOI: 10.2210/pdb9cml/pdb
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform, tert-butyl [2-(2-{[(2P)-2-{4-[4-(2-amino-2-oxoethyl)-2-fluoroanilino]thieno[2,3-d]pyridazin-7-yl}phenyl]oxy}ethoxy)ethyl]carbamate (3 entities in total)
• Functional Keywords: ras, pi3kalpha, p110alpha, pik3ca, rbd, glue, d223, oncoprotein, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 34166.31

Authors

Czyzyk, D.J.,Simanshu, D.K. (deposition date: 2024-07-15, release date: 2025-07-23, Last modification date: 2025-08-06)

Primary citation

Terayama, K.,Furuzono, S.,Fer, N.,Yan, W.,Young, L.C.,Czyzyk, D.J.,Goldstein de Salazar, R.,Sasaki, M.,Uozumi, A.,Konishi, M.,Kanda, S.,Sogawa, Y.,Yamaguchi, M.,Tsuji, T.,Kuroyanagi, J.,Hayashi, M.,Ogura, Y.,Simanshu, D.K.,Kubota, K.,Tanaka, J.,McCormick, F.
Molecular glues that facilitate RAS binding to PI3K alpha promote glucose uptake without insulin.
Science, 389:402-408, 2025

PubMed Abstract: While exploring strategies to control blood glucose concentrations in diabetes, we identified so-called molecular glues D223 and D927 that promote glucose uptake in the absence of insulin. They act by increasing the binding affinity of phosphoinositide 3-kinase α (PI3Kα) catalytic subunit p110α to canonical small guanosine triphosphatase RAS proteins and to RRAS, RRAS2, and MRAS by three orders of magnitude. The compounds bind to the RAS-binding domain of p110α, stabilizing the secondary structures of the PI3Kα in a RAS-binding conformation and forming direct interactions with RAS residues tyrosine-40 and arginine-41. In vivo, D927 mimicked the effects of insulin: It rapidly lowered blood glucose concentrations, enhanced glucose metabolism in normal and Zucker fatty rats, and improved hyperglycemia in models of type 1 and type 2 diabetes, even in insulin-deficient diabetic animals.

PubMed: 40705882
DOI: 10.1126/science.adr9097

Experimental method

X-RAY DIFFRACTION (2.01 Å)