2WXG: The Crystal Structure Of The Murine Class Ia Pi 3-Kinase P110delta In Complex With Sw13

Citation:
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.
PDB ID: 2WXGDownload
MMDB ID: 79167
PDB Deposition Date: 2009/11/9
Updated in MMDB: 2012/12
Experimental Method:
x-ray diffraction
Resolution: 2  Å
Source Organism:
Similar Structures:
Biological Unit for 2WXG: monomeric; determined by author and by software (PISA)
Molecular Components in 2WXG
Label Count Molecule
Protein (1 molecule)
1
Phosphatidylinositol-4,5-bisphosphate 3-kinase Catalytic Subunit Delta Isoform
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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