2qj4: Difference between revisions

Revision as of 19:39, 21 February 2008

A Mechanistic Basis for Converting a Receptor Tyrosine Kinase Agonist to an Antagonist

OverviewOverview

Hepatocyte growth factor (HGF) activates the Met receptor tyrosine kinase by binding and promoting receptor dimerization. Here we describe a mechanistic basis for designing Met antagonists based on NK1, a natural variant of HGF containing the N-terminal and the first kringle domain. Through detailed biochemical and structural analyses, we demonstrate that both mouse and human NK1 induce Met dimerization via a conserved NK1 dimer interface. Mutations designed to alter the NK1 dimer interface abolish its ability to promote Met dimerization but retain full Met-binding activity. Importantly, these NK1 mutants act as Met antagonists by inhibiting HGF-mediated cell scattering, proliferation, branching, and invasion. The ability to separate the Met-binding activity of NK1 from its Met dimerization activity thus provides a rational basis for designing Met antagonists. This strategy of antagonist design may be applicable for other growth factor receptors by selectively abolishing the receptor activation ability but not the receptor binding of the growth factors.

About this StructureAbout this Structure

2QJ4 is a Single protein structure of sequence from Mus musculus with as ligand. Full crystallographic information is available from OCA.

ReferenceReference

A mechanistic basis for converting a receptor tyrosine kinase agonist to an antagonist., Tolbert WD, Daugherty J, Gao C, Xie Q, Miranti C, Gherardi E, Woude GV, Xu HE, Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14592-7. Epub 2007 Sep 5. PMID:17804794

Page seeded by OCA on Thu Feb 21 18:39:41 2008

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OCA

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 ==Overview==
-Hepatocyte growth factor (HGF) activates the Met receptor tyrosine kinase, by binding and promoting receptor dimerization. Here we describe a, mechanistic basis for designing Met antagonists based on NK1, a natural, variant of HGF containing the N-terminal and the first kringle domain., Through detailed biochemical and structural analyses, we demonstrate that, both mouse and human NK1 induce Met dimerization via a conserved NK1 dimer, interface. Mutations designed to alter the NK1 dimer interface abolish its, ability to promote Met dimerization but retain full Met-binding activity., Importantly, these NK1 mutants act as Met antagonists by inhibiting, HGF-mediated cell scattering, proliferation, branching, and invasion. The, ability to separate the Met-binding activity of NK1 from its Met, dimerization activity thus provides a rational basis for designing Met, antagonists. This strategy of antagonist design may be applicable for, other growth factor receptors by selectively abolishing the receptor, activation ability but not the receptor binding of the growth factors.
+Hepatocyte growth factor (HGF) activates the Met receptor tyrosine kinase by binding and promoting receptor dimerization. Here we describe a mechanistic basis for designing Met antagonists based on NK1, a natural variant of HGF containing the N-terminal and the first kringle domain. Through detailed biochemical and structural analyses, we demonstrate that both mouse and human NK1 induce Met dimerization via a conserved NK1 dimer interface. Mutations designed to alter the NK1 dimer interface abolish its ability to promote Met dimerization but retain full Met-binding activity. Importantly, these NK1 mutants act as Met antagonists by inhibiting HGF-mediated cell scattering, proliferation, branching, and invasion. The ability to separate the Met-binding activity of NK1 from its Met dimerization activity thus provides a rational basis for designing Met antagonists. This strategy of antagonist design may be applicable for other growth factor receptors by selectively abolishing the receptor activation ability but not the receptor binding of the growth factors.
 ==About this Structure==
@@ Line 10: / Line 10: @@
 ==Reference==
-A mechanistic basis for converting a receptor tyrosine kinase agonist to an antagonist., Tolbert WD, Daugherty J, Gao C, Xie Q, Miranti C, Gherardi E, Vande Woude G, Xu HE, Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14592-7. Epub 2007 Sep 5. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17804794 17804794]
+A mechanistic basis for converting a receptor tyrosine kinase agonist to an antagonist., Tolbert WD, Daugherty J, Gao C, Xie Q, Miranti C, Gherardi E, Woude GV, Xu HE, Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14592-7. Epub 2007 Sep 5. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17804794 17804794]
 [[Category: Mus musculus]]
 [[Category: Single protein]]
 [[Category: Daugherty, J.]]
-[[Category: Gao, C.F.]]
+[[Category: Gao, C F.]]
 [[Category: Gherardi, E.]]
 [[Category: Miranti, C.]]
-[[Category: Tolbert, W.D.]]
+[[Category: Tolbert, W D.]]
-[[Category: Woude, G.Vande.]]
+[[Category: Woude, G Vande.]]
 [[Category: Xe, Q.]]
-[[Category: Xu, H.E.]]
+[[Category: Xu, H E.]]
 [[Category: SO4]]
 [[Category: hgf/sf]]
 [[Category: hormone/growth factor]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 13:35:20 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:39:41 2008''