2i0y
From Proteopedia
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|PDB= 2i0y |SIZE=350|CAPTION= <scene name='initialview01'>2i0y</scene>, resolution 1.90Å | |PDB= 2i0y |SIZE=350|CAPTION= <scene name='initialview01'>2i0y</scene>, resolution 1.90Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=5CN:5-CYANO-FURAN-2-CARBOXYLIC ACID [5-HYDROXYMETHYL-2-(4-METHYL-PIPERIDIN-1-YL)-PHENYL]-AMIDE'>5CN</scene> | + | |LIGAND= <scene name='pdbligand=5CN:5-CYANO-FURAN-2-CARBOXYLIC+ACID+[5-HYDROXYMETHYL-2-(4-METHYL-PIPERIDIN-1-YL)-PHENYL]-AMIDE'>5CN</scene> |
| - | |ACTIVITY= [http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] | + | |ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span> |
|GENE= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[2i0v|2I0V]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2i0y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2i0y OCA], [http://www.ebi.ac.uk/pdbsum/2i0y PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2i0y RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
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. | 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. | ||
| - | |||
| - | ==Disease== | ||
| - | Known diseases associated with this structure: Myeloid malignancy, predisposition to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=164770 164770]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Schalk-Hihi, C.]] | [[Category: Schalk-Hihi, C.]] | ||
[[Category: Schubert, C.]] | [[Category: Schubert, C.]] | ||
| - | [[Category: 5CN]] | ||
[[Category: kinase inhibitor complex]] | [[Category: kinase inhibitor complex]] | ||
[[Category: transferase]] | [[Category: transferase]] | ||
[[Category: tyrosine kinase]] | [[Category: tyrosine kinase]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:38:13 2008'' |
Revision as of 00:38, 31 March 2008
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| , resolution 1.90Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | |||||||
| Activity: | Receptor protein-tyrosine kinase, with EC number 2.7.10.1 | ||||||
| Related: | 2I0V
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
cFMS tyrosine kinase (FGF KID) in complex with an arylamide inhibitor
Overview
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.
About this Structure
2I0Y is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Crystal structure of the tyrosine kinase domain of colony-stimulating factor-1 receptor (cFMS) in complex with two inhibitors., Schubert C, Schalk-Hihi C, Struble GT, Ma HC, Petrounia IP, Brandt B, Deckman IC, Patch RJ, Player MR, Spurlino JC, Springer BA, J Biol Chem. 2007 Feb 9;282(6):4094-101. Epub 2006 Nov 28. PMID:17132624
Page seeded by OCA on Mon Mar 31 03:38:13 2008
