2ivt

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[[Image:2ivt.gif|left|200px]]
[[Image:2ivt.gif|left|200px]]
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{{Structure
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<!--
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|PDB= 2ivt |SIZE=350|CAPTION= <scene name='initialview01'>2ivt</scene>, resolution 2.60&Aring;
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The line below this paragraph, containing "STRUCTURE_2ivt", creates the "Structure Box" on the page.
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|SITE= <scene name='pdbsite=AC1:Amp+Binding+Site+For+Chain+A'>AC1</scene>
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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|LIGAND= <scene name='pdbligand=AMP:ADENOSINE+MONOPHOSPHATE'>AMP</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene>
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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|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>
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or leave the SCENE parameter empty for the default display.
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|GENE=
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-->
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|DOMAIN=
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{{STRUCTURE_2ivt| PDB=2ivt | SCENE= }}
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|RELATEDENTRY=
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ivt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ivt OCA], [http://www.ebi.ac.uk/pdbsum/2ivt PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2ivt RCSB]</span>
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}}
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'''CRYSTAL STRUCTURE OF PHOSPHORYLATED RET TYROSINE KINASE DOMAIN'''
'''CRYSTAL STRUCTURE OF PHOSPHORYLATED RET TYROSINE KINASE DOMAIN'''
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[[Category: Mcdonald, N Q.]]
[[Category: Mcdonald, N Q.]]
[[Category: Murray-Rust, J.]]
[[Category: Murray-Rust, J.]]
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[[Category: atp-binding]]
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[[Category: Atp-binding]]
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[[Category: chromosomal translocation]]
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[[Category: Chromosomal translocation]]
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[[Category: disease mutation]]
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[[Category: Disease mutation]]
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[[Category: gdnf receptor]]
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[[Category: Gdnf receptor]]
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[[Category: hirschsprung disease]]
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[[Category: Hirschsprung disease]]
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[[Category: kinase]]
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[[Category: Kinase]]
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[[Category: membrane]]
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[[Category: Membrane]]
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[[Category: nucleotide-binding]]
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[[Category: Nucleotide-binding]]
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[[Category: phosphorylation]]
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[[Category: Phosphorylation]]
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[[Category: phosphotransferase]]
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[[Category: Phosphotransferase]]
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[[Category: polymorphism]]
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[[Category: Polymorphism]]
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[[Category: proto-oncogene]]
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[[Category: Proto-oncogene]]
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[[Category: ret]]
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[[Category: Ret]]
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[[Category: transferase]]
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[[Category: Transferase]]
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[[Category: transmembrane]]
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[[Category: Transmembrane]]
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[[Category: tyrosine kinase]]
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[[Category: Tyrosine kinase]]
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[[Category: tyrosine-protein kinase]]
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[[Category: Tyrosine-protein kinase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 07:56:48 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:49:16 2008''
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Revision as of 04:56, 4 May 2008

Image:2ivt.gif

Template:STRUCTURE 2ivt

CRYSTAL STRUCTURE OF PHOSPHORYLATED RET TYROSINE KINASE DOMAIN


Overview

The RET proto-oncogene encodes a receptor tyrosine kinase for the glial cell line-derived neurotrophic factor family of ligands. Loss-of-function mutations in RET are implicated in Hirschsprung disease, whereas activating mutations in RET are found in human cancers, including familial medullar thyroid carcinoma and multiple endocrine neoplasias 2A and 2B. We report here the biochemical characterization of the human RET tyrosine kinase domain and the structure determination of the non-phosphorylated and phosphorylated forms. Both structures adopt the same active kinase conformation competent to bind ATP and substrate and have a pre-organized activation loop conformation that is independent of phosphorylation status. In agreement with the structural data, enzyme kinetic data show that autophosphorylation produces only a modest increase in activity. Longer forms of RET containing the juxtamembrane domain and C-terminal tail exhibited similar kinetic behavior, implying that there is no cis-inhibitory mechanism within the RET intracellular domain. Our results suggest the existence of alternative inhibitory mechanisms, possibly in trans, for the autoregulation of RET kinase activity. We also present the structures of the RET tyrosine kinase domain bound to two inhibitors, the pyrazolopyrimidine PP1 and the clinically relevant 4-anilinoquinazoline ZD6474. These structures explain why certain multiple endocrine neoplasia 2-associated RET mutants found in patients are resistant to inhibition and form the basis for design of more effective inhibitors.

About this Structure

2IVT is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Structure and chemical inhibition of the RET tyrosine kinase domain., Knowles PP, Murray-Rust J, Kjaer S, Scott RP, Hanrahan S, Santoro M, Ibanez CF, McDonald NQ, J Biol Chem. 2006 Nov 3;281(44):33577-87. Epub 2006 Aug 23. PMID:16928683 Page seeded by OCA on Sun May 4 07:56:48 2008

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