2ivu

File:2ivu.gif

spinqualitylabelsall models 2ivu, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

CRYSTAL STRUCTURE OF PHOSPHORYLATED RET TYROSINE KINASE DOMAIN COMPLEXED WITH THE INHIBITOR ZD6474

OverviewOverview

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.

DiseaseDisease

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 StructureAbout this Structure

2IVU is a Single protein structure of sequence from Homo sapiens with ZD6 and FMT as ligands. Active as Receptor protein-tyrosine kinase, with EC number 2.7.10.1 Known structural/functional Site: . Full crystallographic information is available from OCA.

ReferenceReference

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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