2CHX
A pharmacological map of the PI3-K family defines a role for p110alpha in signaling: The structure of complex of phosphoinositide 3-kinase gamma with inhibitor PIK-90
Summary for 2CHX
| Entry DOI | 10.2210/pdb2chx/pdb |
| Related | 1E8Y 1E8Z 1HE8 2A4Z 2A5U 2CHW 2CHZ |
| Descriptor | PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT GAMMA ISOFORM, N-(2,3-DIHYDRO-7,8-DIMETHOXYIMIDAZO[1,2-C] QUINAZOLIN-5-YL)NICOTINAMIDE (2 entities in total) |
| Functional Keywords | phosphoinositide, kinase, lipid, inhibitor, 3-kinase, signaling, quinazolinone, transferase |
| Biological source | HOMO SAPIENS (HUMAN) |
| Total number of polymer chains | 1 |
| Total formula weight | 111106.51 |
| Authors | Knight, Z.A.,Gonzalez, B.,Feldman, M.E.,Zunder, E.R.,Goldenberg, D.D.,Williams, O.,Loewith, R.,Stokoe, D.,Balla, A.,Toth, B.,Balla, T.,Weiss, W.A.,Williams, R.L.,Shokat, K.M. (deposition date: 2006-03-16, release date: 2006-05-22, Last modification date: 2023-12-13) |
| Primary citation | Knight, Z.A.,Gonzalez, B.,Feldman, M.E.,Zunder, E.R.,Goldenberg, D.D.,Williams, O.,Loewith, R.,Stokoe, D.,Balla, A.,Toth, B.,Balla, T.,Weiss, W.A.,Williams, R.L.,Shokat, K.M. A Pharmacological Map of the Pi3-K Family Defines a Role for P110Alpha in Signaling Cell(Cambridge,Mass.), 125:733-, 2006 Cited by PubMed Abstract: Phosphoinositide 3-kinases (PI3-Ks) are an important emerging class of drug targets, but the unique roles of PI3-K isoforms remain poorly defined. We describe here an approach to pharmacologically interrogate the PI3-K family. A chemically diverse panel of PI3-K inhibitors was synthesized, and their target selectivity was biochemically enumerated, revealing cryptic homologies across targets and chemotypes. Crystal structures of three inhibitors bound to p110gamma identify a conformationally mobile region that is uniquely exploited by selective compounds. This chemical array was then used to define the PI3-K isoforms required for insulin signaling. We find that p110alpha is the primary insulin-responsive PI3-K in cultured cells, whereas p110beta is dispensable but sets a phenotypic threshold for p110alpha activity. Compounds targeting p110alpha block the acute effects of insulin treatment in vivo, whereas a p110beta inhibitor has no effect. These results illustrate systematic target validation using a matrix of inhibitors that span a protein family. PubMed: 16647110DOI: 10.1016/J.CELL.2006.03.035 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.5 Å) |
Structure validation
Download full validation report
