2ivt

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[[Image:2ivt.gif|left|200px]]<br /><applet load="2ivt" size="350" color="white" frame="true" align="right" spinBox="true"
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[[Image:2ivt.gif|left|200px]]
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caption="2ivt, resolution 2.60&Aring;" />
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'''CRYSTAL STRUCTURE OF PHOSPHORYLATED RET TYROSINE KINASE DOMAIN'''<br />
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{{Structure
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|PDB= 2ivt |SIZE=350|CAPTION= <scene name='initialview01'>2ivt</scene>, resolution 2.60&Aring;
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|SITE= <scene name='pdbsite=AC1:Amp+Binding+Site+For+Chain+A'>AC1</scene>
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|LIGAND= <scene name='pdbligand=AMP:ADENOSINE+MONOPHOSPHATE'>AMP</scene> and <scene name='pdbligand=FMT:FORMIC ACID'>FMT</scene>
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|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]
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|GENE=
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}}
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'''CRYSTAL STRUCTURE OF PHOSPHORYLATED RET TYROSINE KINASE DOMAIN'''
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==Overview==
==Overview==
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==About this Structure==
==About this Structure==
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2IVT is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=AMP:'>AMP</scene> and <scene name='pdbligand=FMT:'>FMT</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Known structural/functional Site: <scene name='pdbsite=AC1:Amp+Binding+Site+For+Chain+A'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2IVT OCA].
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2IVT is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2IVT OCA].
==Reference==
==Reference==
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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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16928683 16928683]
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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:[http://www.ncbi.nlm.nih.gov/pubmed/16928683 16928683]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Receptor protein-tyrosine kinase]]
[[Category: Receptor protein-tyrosine kinase]]
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[[Category: tyrosine-protein kinase]]
[[Category: tyrosine-protein kinase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:56:29 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 17:33:56 2008''

Revision as of 15:33, 20 March 2008

Image:2ivt.gif


PDB ID 2ivt

Drag the structure with the mouse to rotate
, resolution 2.60Å
Sites:
Ligands: and
Activity: Receptor protein-tyrosine kinase, with EC number 2.7.10.1
Coordinates: save as pdb, mmCIF, xml



CRYSTAL STRUCTURE OF PHOSPHORYLATED RET TYROSINE KINASE DOMAIN


Contents

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.

Disease

Known diseases associated with this structure: Central hypoventilation syndrome, congenital OMIM:[164761], Hirschsprung disease OMIM:[164761], Medullary thyroid carcinoma OMIM:[164761], Multiple endocrine neoplasia IIA OMIM:[164761], Multiple endocrine neoplasia IIB OMIM:[164761], Pheochromocytoma OMIM:[164761]

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

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