2X38

The crystal structure of the murine class IA PI 3-kinase p110delta in complex with IC87114.

Replaces:  2WXE

Summary for 2X38

• Entry DOI: 10.2210/pdb2x38/pdb
• Descriptor: PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT DELTA ISOFORM, 2-[(6-AMINO-9H-PURIN-9-YL)METHYL]-5-METHYL-3-(2-METHYLPHENYL)QUINAZOLIN-4(3H)-ONE (3 entities in total)
• Functional Keywords: phosphoinositide 3-kinase, isoform-specific inhibitors, cancer, transferase
• Biological source: MUS MUSCULUS (MOUSE)
• Total number of polymer chains: 1
• Total formula weight: 108221.10

Authors

Berndt, A.,Miller, S.,Williams, O.,Lee, D.D.,Houseman, B.T.,Pacold, J.I.,Gorrec, F.,Hon, W.-C.,Liu, Y.,Rommel, C.,Gaillard, P.,Ruckle, T.,Schwarz, M.K.,Shokat, K.M.,Shaw, J.P.,Williams, R.L. (deposition date: 2010-01-22, release date: 2010-02-02, Last modification date: 2023-12-20)

Primary citation

Berndt, A.,Miller, S.,Williams, O.,Lee, D.D.,Houseman, B.T.,Pacold, J.I.,Gorrec, F.,Hon, W.-C.,Liu, Y.,Rommel, C.,Gaillard, P.,Ruckle, T.,Schwarz, M.K.,Shokat, K.M.,Shaw, J.P.,Williams, R.L.
The P110D Structure: Mechanisms for Selectivity and Potency of New Pi(3)K Inhibitors
Nat.Chem.Biol., 6:117-, 2010

PubMed Abstract: Deregulation of the phosphoinositide-3-OH kinase (PI(3)K) pathway has been implicated in numerous pathologies including cancer, diabetes, thrombosis, rheumatoid arthritis and asthma. Recently, small-molecule and ATP-competitive PI(3)K inhibitors with a wide range of selectivities have entered clinical development. In order to understand the mechanisms underlying the isoform selectivity of these inhibitors, we developed a new expression strategy that enabled us to determine to our knowledge the first crystal structure of the catalytic subunit of the class IA PI(3)K p110 delta. Structures of this enzyme in complex with a broad panel of isoform- and pan-selective class I PI(3)K inhibitors reveal that selectivity toward p110 delta can be achieved by exploiting its conformational flexibility and the sequence diversity of active site residues that do not contact ATP. We have used these observations to rationalize and synthesize highly selective inhibitors for p110 delta with greatly improved potencies.

PubMed: 20081827
DOI: 10.1038/NCHEMBIO.293

Experimental method

X-RAY DIFFRACTION (2.2 Å)