title: A mechanistic basis for converting a receptor tyrosine kinase agonist to an antagonist.
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.
authors.affiliation: Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue, Grand Rapids, MI 49503, USA.
authors.forename: W David
authors.initials: WD
authors.lastname: Tolbert
authors.forename: Jennifer
authors.initials: J
authors.lastname: Daugherty
authors.forename: ChongFeng
authors.initials: C
authors.lastname: Gao
authors.forename: Qian
authors.initials: Q
authors.lastname: Xie
authors.forename: Cindy
authors.initials: C
authors.lastname: Miranti
authors.forename: Ermanno
authors.initials: E
authors.lastname: Gherardi
authors.forename: George
authors.initials: G
authors.lastname: Vande Woude
authors.forename: H Eric
authors.initials: HE
authors.lastname: Xu
mesh_terms: D000818:Animals; D002460:Cell Line; D019281:Dimerization; D004220:Disulfides / Q000737:chemistry; D004285:Dogs; D004926:Escherichia coli / Q000235:genetics; D006493:Heparin / Q000494:pharmacology; D017228:Hepatocyte Growth Factor / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006639:Histidine / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000166:cytology; D018082:Kringles; D008027:Light; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D009842:Oligopeptides / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D019859:Proto-Oncogene Proteins c-met / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012542:Scattering, Radiation; D014961:X-Ray Diffraction