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 p110δ. 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 p110δ 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 p110δ with greatly improved potencies.
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Protein Data Bank
We thank the beamline scientists and members of staff at the European Synchrotron Radiation Facility beamlines ID14-1, ID14-2, ID14-4, ID23-1, ID29 and BM30A (Grenoble, France), the Swiss Light Source beamline X06SA (Villigen, Switzerland) and the Diamond beamline I02 (Oxfordshire, UK). We are grateful to M. Allen for collecting the p110δ-ZSTK474 dataset and to O. Perisic for her help with the manuscript and for numerous contributions to this study. Part of this material is based on work supported under a US National Science Foundation Graduate Research Fellowship to O.W. and was supported by the Graduate Research and Education in Adaptive bio-Technology Training Program of the University of California Systemwide Biotechnology Research and Education Program, grant number 2008-005 to O.W. A.B. is supported by Merck-Serono, Geneva.
Movie morphing between the apo- and PIK-39-bound structures of p110δ.
The movie illustrates frames from a 20ns molecular dynamics simulation for the isolated p110γ catalytic domain, which is rendered as a cartoon with residues Met804 (right), Trp812 (middle) and Glu814 (left) shown in a stick representation.
Movie illustrating frames from a 20ns molecular dynamics simulation for the isolated p110δ catalytic domain, which is rendered as a cartoon with residues Met752 (right), Trp760 (middle) and Met762 (left) shown in a stick representation.