2QJ2
A Mechanistic Basis for Converting a Receptor Tyrosine Kinase Agonist to an Antagonist
Summary for 2QJ2
| Entry DOI | 10.2210/pdb2qj2/pdb |
| Related | 1BHT 1GMN 1GMO 1GP9 1NK1 2HGF 2QJ4 |
| Descriptor | Hepatocyte growth factor, SULFATE ION (3 entities in total) |
| Functional Keywords | hgf/sf, hormone/growth factor, hormone |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 42702.72 |
| Authors | Tolbert, W.D.,Daugherty, J.,Gao, C.-F.,Xe, Q.,Miranti, C.,Gherardi, E.,Vande Woude, G.,Xu, H.E. (deposition date: 2007-07-06, release date: 2007-09-18, Last modification date: 2024-10-16) |
| Primary citation | Tolbert, W.D.,Daugherty, J.,Gao, C.,Xie, Q.,Miranti, C.,Gherardi, E.,Vande Woude, G.,Xu, H.E. A mechanistic basis for converting a receptor tyrosine kinase agonist to an antagonist Proc.Natl.Acad.Sci.Usa, 104:14592-14597, 2007 Cited by PubMed Abstract: 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. PubMed: 17804794DOI: 10.1073/pnas.0704290104 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.81 Å) |
Structure validation
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