2I1M

cFMS tyrosine kinase (tie2 KID) in complex with an arylamide inhibitor

Summary for 2I1M

• Entry DOI: 10.2210/pdb2i1m/pdb
• Related: 2I0V 2I0Y
• Descriptor: Macrophage colony-stimulating factor 1 receptor, 5-CYANO-FURAN-2-CARBOXYLIC ACID [5-HYDROXYMETHYL-2-(4-METHYL-PIPERIDIN-1-YL)-PHENYL]-AMIDE (3 entities in total)
• Functional Keywords: kinase domain, kinase inhibitor complex, transferase
• Biological source: Homo sapiens (human); More
• Cellular location: Cell membrane; Single-pass type I membrane protein: P07333
• Total number of polymer chains: 1
• Total formula weight: 37952.45

Authors

Schubert, C.,Schalk-Hihi, C. (deposition date: 2006-08-14, release date: 2006-11-28, Last modification date: 2024-02-21)

Primary citation

Schubert, C.,Schalk-Hihi, C.,Struble, G.T.,Ma, H.C.,Petrounia, I.P.,Brandt, B.,Deckman, I.C.,Patch, R.J.,Player, M.R.,Spurlino, J.C.,Springer, B.A.
Crystal structure of the tyrosine kinase domain of colony-stimulating factor-1 receptor (cFMS) in complex with two inhibitors.
J.Biol.Chem., 282:4094-4101, 2007

PubMed 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.

PubMed: 17132624
DOI: 10.1074/jbc.M608183200

Experimental method

X-RAY DIFFRACTION (1.8 Å)