3b2t

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{{STRUCTURE_3b2t| PDB=3b2t | SCENE= }}
{{STRUCTURE_3b2t| PDB=3b2t | SCENE= }}
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'''Structure of phosphotransferase'''
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===Structure of phosphotransferase===
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==Overview==
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Mutations in fibroblast growth factor receptor 2 (FGFR2) and its ligand, FGF10, are known to cause lacrimo-auriculo-dento-digital (LADD) syndrome. Multiple gain-of-function mutations in FGF receptors have been implicated in a variety of severe skeletal disorders and in many cancers. We aimed to elucidate the mechanism by which a missense mutation in the tyrosine kinase domain of FGFR2, described in the sporadic case of LADD syndrome, leads to reduced tyrosine kinase activity. In this report, we describe the crystal structure of a FGFR2 A628T LADD mutant in complex with a nucleotide analog. We demonstrate that the A628T LADD mutation alters the configuration of key residues in the catalytic pocket that are essential for substrate coordination, resulting in reduced tyrosine kinase activity. Further comparison of the structures of WT FGFR2 and WT FGFR1 kinases revealed that FGFR2 uses a less stringent mode of autoinhibition than FGFR1, which was also manifested in faster in vitro autophosphorylation kinetics. Moreover, the nearly identical conformation of WT FGFR2 kinase and the A628T LADD mutant to either the phosphorylated FGFR2 or FGFR2 harboring pathological activating mutations in the kinase hinge region suggests that FGFR autoinhibition and activation are better explained by changes in the conformational dynamics of the kinase rather than by static crystallographic snapshots of minor structural variations.
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{{ABSTRACT_PUBMED_18056630}}
==About this Structure==
==About this Structure==
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[[Category: Transmembrane]]
[[Category: Transmembrane]]
[[Category: Tyrosine-protein kinase]]
[[Category: Tyrosine-protein kinase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 20:20:05 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 18:55:55 2008''

Revision as of 15:56, 27 July 2008

Image:3b2t.png

Template:STRUCTURE 3b2t

Structure of phosphotransferase

Template:ABSTRACT PUBMED 18056630

About this Structure

3B2T is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Structural basis for reduced FGFR2 activity in LADD syndrome: Implications for FGFR autoinhibition and activation., Lew ED, Bae JH, Rohmann E, Wollnik B, Schlessinger J, Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19802-7. Epub 2007 Dec 3. PMID:18056630

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