title: Classifying protein kinase structures guides use of ligand-selectivity profiles to predict inactive conformations: structure of lck/imatinib complex.
abstract: We report a clustering of public human protein kinase structures based on the conformations of two structural elements, the activation segment and the C-helix, revealing three discrete clusters. One cluster includes kinases in catalytically active conformations. Each of the other clusters contains a distinct inactive conformation. Typically, kinases adopt at most one of the inactive conformations in available X-ray structures, implying that one of the conformations is preferred for many kinases. The classification is consistent with selectivity profiles of several well-characterized kinase inhibitors. We show further that inhibitor selectivity profiles guide kinase classification. For example, selective inhibition of lck among src-family kinases by imatinib (Gleevec) suggests that the relative stabilities of inactive conformations of lck are different from other src-family kinases. We report the X-ray structure of the lck/imatinib complex, confirming that the conformation adopted by lck is distinct from other structurally-characterized src-family kinases and instead resembles kinases abl1 and kit in complex with imatinib. Our classification creates new paths for designing small-molecule inhibitors.
authors.affiliation: Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, Massachusetts 02139, USA.
authors.forename: Marc D
authors.initials: MD
authors.lastname: Jacobs
authors.forename: Paul R
authors.initials: PR
authors.lastname: Caron
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Hare
mesh_terms: D001549:Benzamides; D002965:Classification; D018360:Crystallography, X-Ray; D006801:Humans; D000068877:Imatinib Mesylate; D008024:Ligands; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000737:chemistry*; D010879:Piperazines / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D011494:Protein Kinases / Q000737:chemistry* / Q000145:classification; D011743:Pyrimidines / Q000737:chemistry*
chemical_list: D001549:Benzamides; D008024:Ligands; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011494:Protein Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)