title: Crystal structure of the tyrosine kinase domain of colony-stimulating factor-1 receptor (cFMS) in complex with two inhibitors.
abstract: The cFMS proto-oncogene encodes for the colony-stimulating factor-1 receptor, a receptor-tyrosine kinase responsible for the differentiation and maturation of certain macrophages. Upon binding its ligand colony-stimulating factor-1 cFMS autophosphorylates, dimerizes, and induces phosphorylation of downstream targets. We report the novel crystal structure of unphosphorylated cFMS in complex with two members of different classes of drug-like protein kinase inhibitors. cFMS exhibits a typical bi-lobal kinase fold, and its activation loop and DFG motif are found to be in the canonical inactive conformation. Both ATP competitive inhibitors are bound in the active site and demonstrate a binding mode similar to that of STI-571 bound to cABL. The DFG motif is prevented from switching into the catalytically competent conformation through interactions with the inhibitors. Activation of cFMS is also inhibited by the juxtamembrane domain, which interacts with residues of the active site and prevents formation of the activated kinase. Together the structures of cFMS provide further insight into the autoinhibition of receptor-tyrosine kinases via their respective juxtamembrane domains; additionally the binding mode of two novel classes of kinase inhibitors will guide the design of novel molecules targeting macrophage-related diseases.
authors.affiliation: Structural Biology, Johnson & Johnson Pharmaceuticals Research and Development, LLC, Exton, Pennsylvania 19341, USA. cschuber@prdus.jnj.com
authors.forename: Carsten
authors.initials: C
authors.lastname: Schubert
authors.forename: Céline
authors.initials: C
authors.lastname: Schalk-Hihi
authors.forename: Geoffrey T
authors.initials: GT
authors.lastname: Struble
authors.forename: Hong-Chang
authors.initials: HC
authors.lastname: Ma
authors.forename: Ioanna P
authors.initials: IP
authors.lastname: Petrounia
authors.forename: Benjamin
authors.initials: B
authors.lastname: Brandt
authors.forename: Ingrid C
authors.initials: IC
authors.lastname: Deckman
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Patch
authors.forename: Mark R
authors.initials: MR
authors.lastname: Player
authors.forename: John C
authors.initials: JC
authors.lastname: Spurlino
authors.forename: Barry A
authors.initials: BA
authors.lastname: Springer
mesh_terms: D000577:Amides / Q000737:chemistry; D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D008969:Molecular Sequence Data; D050506:Mutant Chimeric Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D017434:Protein Structure, Tertiary / Q000235:genetics; D000090063:Proto-Oncogene Mas; D015363:Quinolones / Q000737:chemistry; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000737:chemistry / Q000235:genetics; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry / Q000235:genetics
chemical_list: D000577:Amides; C000715470:MAS1 protein, human; D050506:Mutant Chimeric Proteins; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D015363:Quinolones; D017468:Receptors, Fibroblast Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D016186:Receptor, Macrophage Colony-Stimulating Factor; D042787:Receptor, TIE-2