Novel protein kinases and molecular mechanisms of autoinhibition.
During the past year, crystal structures of the PDK-1, ITK, Aurora-A, c-KIT and FLT-3 protein kinases in complex with several ATP-competitive inhibitors have been determined. Some structures have crystallized in catalytically active conformations, whereas others appear to be in inactive or native conformations. The differences between these two classes of structures provide further understanding of how kinase activity may be self-regulated in the cellular environment and how phosphorylation can modulate signalling at a molecular level. All of these structures provide a basis for designing selective protein kinase inhibitors of use in the treatment of cancer and autoimmune disease.
Cheetham
Graham M T
GM
Vertex Pharmaceuticals (Europe) Ltd, 88 Milton Park, Abingdon, Oxfordshire OX14 4RY, UK. graham_cheetham@vrtx.com
D000818:Animals; D001665:Binding Sites; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000145:classification / Q000378:metabolism; D008938:Mitosis / Q000502:physiology; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D011494:Protein Kinases / Q000737:chemistry* / Q000145:classification / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011494:Protein Kinases; D020794:Receptor Protein-Tyrosine Kinases