2qj2
From Proteopedia
(New page: 200px<br /> <applet load="2qj2" size="450" color="white" frame="true" align="right" spinBox="true" caption="2qj2, resolution 1.81Å" /> '''A Mechanistic Basis...) |
|||
| Line 1: | Line 1: | ||
| - | [[Image:2qj2.gif|left|200px]]<br /> | + | [[Image:2qj2.gif|left|200px]]<br /><applet load="2qj2" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="2qj2" size=" | + | |
caption="2qj2, resolution 1.81Å" /> | caption="2qj2, resolution 1.81Å" /> | ||
'''A Mechanistic Basis for Converting a Receptor Tyrosine Kinase Agonist to an Antagonist'''<br /> | '''A Mechanistic Basis for Converting a Receptor Tyrosine Kinase Agonist to an Antagonist'''<br /> | ||
| Line 6: | Line 5: | ||
==Overview== | ==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. | ||
| - | |||
| - | ==Disease== | ||
| - | Known diseases associated with this structure: Fibromatosis, gingival OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=182530 182530]], Noonan syndrome 4 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=182530 182530]] | ||
==About this Structure== | ==About this Structure== | ||
| - | 2QJ2 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 SO4 as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 2QJ2 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=SO4:'>SO4</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QJ2 OCA]. |
==Reference== | ==Reference== | ||
| Line 29: | Line 25: | ||
[[Category: hormone/growth factor]] | [[Category: hormone/growth factor]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 13:35:18 2008'' |
Revision as of 11:35, 23 January 2008
|
A Mechanistic Basis for Converting a Receptor Tyrosine Kinase Agonist to an Antagonist
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.
About this Structure
2QJ2 is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
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:17804794
Page seeded by OCA on Wed Jan 23 13:35:18 2008
