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2i1m

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{{STRUCTURE_2i1m| PDB=2i1m | SCENE= }}
{{STRUCTURE_2i1m| PDB=2i1m | SCENE= }}
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'''cFMS tyrosine kinase (tie2 KID) in complex with an arylamide inhibitor'''
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===cFMS tyrosine kinase (tie2 KID) in complex with an arylamide inhibitor===
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==Overview==
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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.
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(as it appears on PubMed at http://www.pubmed.gov), where 17132624 is the PubMed ID number.
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{{ABSTRACT_PUBMED_17132624}}
==Disease==
==Disease==
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[[Category: Kinase domain]]
[[Category: Kinase domain]]
[[Category: Kinase inhibitor complex]]
[[Category: Kinase inhibitor complex]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 06:58:00 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 06:10:18 2008''

Revision as of 03:10, 29 July 2008

Image:2i1m.png

Template:STRUCTURE 2i1m

Contents

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

Template:ABSTRACT PUBMED 17132624

Disease

Known disease associated with this structure: Myeloid malignancy, predisposition to OMIM:[164770]

About this Structure

2I1M 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

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