title: X-ray crystal structure of bone marrow kinase in the x chromosome: a Tec family kinase.
abstract: Bone marrow kinase in the X chromosome, a member of the Tec family of tyrosine kinases, plays a role in both monocyte/macrophage trafficking as well as cytokine secretion. Although the structures of Tec family kinases Bruton's tyrosine kinase and IL-2-inducible T-cell kinase are known, the crystal structures of other Tec family kinases have remained elusive. We report the X-ray crystal structures of bone marrow kinase in the X chromosome in complex with dasatinib at 2.4 Å resolution and PP2 at 1.9 Å resolution. The bone marrow kinase in the X chromosome structures reveal a typical kinase protein fold; with well-ordered protein conformation that includes an open/extended activation loop and a stabilized DFG-motif rendering the kinase in an inactive conformation. Dasatinib and PP2 bind to bone marrow kinase in the X chromosome in the ATP binding pocket and display similar binding modes to that observed in other Tec and Src protein kinases. The bone marrow kinase in the X chromosome structures identify conformational elements of the DFG-motif that could potentially be utilized to design potent and/or selective bone marrow kinase in the X chromosome inhibitors.
authors: Chemical and Protein Technologies, Bristol-Myers Squibb, PO Box 4000, Princeton, NJ 08543, USA. jodi.muckelbauer@bms.com
authors: Jodi
authors: J
authors: Muckelbauer
authors: John S
authors: JS
authors: Sack
authors: Nazia
authors: N
authors: Ahmed
authors: James
authors: J
authors: Burke
authors: Chiehying Y
authors: CY
authors: Chang
authors: Mian
authors: M
authors: Gao
authors: Joseph
authors: J
authors: Tino
authors: Dianlin
authors: D
authors: Xie
authors: Andrew J
authors: AJ
authors: Tebben
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D001665:Binding Sites; D041321:Chromosomes, Human, X; D018360:Crystallography, X-Ray; D000069439:Dasatinib; D006801:Humans; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry* / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry; D013844:Thiazoles / Q000737:chemistry; D019061:src-Family Kinases / Q000737:chemistry / Q000378:metabolism
chemical_list: C412373:AG 1879; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C080813:emt protein-tyrosine kinase; D019061:src-Family Kinases; D000069439:Dasatinib