2Y3A

Crystal structure of p110beta in complex with icSH2 of p85beta and the drug GDC-0941

Summary for 2Y3A

• Entry DOI: 10.2210/pdb2y3a/pdb
• Descriptor: PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT BETA ISOFORM, PHOSPHATIDYLINOSITOL 3-KINASE REGULATORY SUBUNIT BETA, 2-(1H-indazol-4-yl)-6-{[4-(methylsulfonyl)piperazin-1-yl]methyl}-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (3 entities in total)
• Functional Keywords: transferase, phosphoinositide 3-kinase, rtk
• Biological source: MUS MUSCULUS (MOUSE); More
• Total number of polymer chains: 2
• Total formula weight: 161102.28

Authors

Zhang, X.,Vadas, O.,Perisic, O.,Williams, R.L. (deposition date: 2010-12-20, release date: 2011-03-16, Last modification date: 2023-12-20)

Primary citation

Zhang, X.,Vadas, O.,Perisic, O.,Anderson, K.E.,Clark, J.,Hawkins, P.T.,Stephens, L.R.,Williams, R.L.
Structure of Lipid Kinase P110Beta-P85Beta Elucidates an Unusual Sh2-Domain-Mediated Inhibitory Mechanism.
Mol.Cell, 41:567-, 2011

PubMed Abstract: Phosphoinositide 3-kinases (PI3Ks) are essential for cell growth, migration, and survival. The structure of a p110β/p85β complex identifies an inhibitory function for the C-terminal SH2 domain (cSH2) of the p85 regulatory subunit. Mutagenesis of a cSH2 contact residue activates downstream signaling in cells. This inhibitory contact ties up the C-terminal region of the p110β catalytic subunit, which is essential for lipid kinase activity. In vitro, p110β basal activity is tightly restrained by contacts with three p85 domains: the cSH2, nSH2, and iSH2. RTK phosphopeptides relieve inhibition by nSH2 and cSH2 using completely different mechanisms. The binding site for the RTK's pYXXM motif is exposed on the cSH2, requiring an extended RTK motif to reach and disrupt the inhibitory contact with p110β. This contrasts with the nSH2 where the pY-binding site itself forms the inhibitory contact. This establishes an unusual mechanism by which p85 SH2 domains contribute to RTK signaling specificities.

PubMed: 21362552
DOI: 10.1016/J.MOLCEL.2011.01.026

Experimental method

X-RAY DIFFRACTION (3.3 Å)