2ivs: Difference between revisions
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==Overview== | ==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, ... | 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== | ==About this Structure== | ||
2IVS is a | 2IVS 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 ACK and FMT 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] Structure known Active Site: AC1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2IVS OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: tyrosine-protein kinase]] | [[Category: tyrosine-protein kinase]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 5 13:46:34 2007'' | ||
