GONUTS has been updated to MW1.31 Most things seem to be working but be sure to report problems.

Have any questions? Please email us at ecoliwiki@gmail.com

PMID:17804794

From GONUTS
Jump to: navigation, search
Citation

Tolbert, WD, Daugherty, J, Gao, C, Xie, Q, Miranti, C, Gherardi, E, Vande Woude, G and Xu, HE (2007) A mechanistic basis for converting a receptor tyrosine kinase agonist to an antagonist. Proc. Natl. Acad. Sci. U.S.A. 104:14592-7

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.

Links

PubMed PMC1965485 Online version:10.1073/pnas.0704290104

Keywords

Animals; Cell Line; Dimerization; Disulfides/chemistry; Dogs; Escherichia coli/genetics; Heparin/pharmacology; Hepatocyte Growth Factor/agonists; Hepatocyte Growth Factor/antagonists & inhibitors; Hepatocyte Growth Factor/chemistry; Hepatocyte Growth Factor/genetics; Hepatocyte Growth Factor/metabolism; Histidine/chemistry; Humans; Inhibitory Concentration 50; Kidney/cytology; Kringles; Light; Mice; Models, Biological; Mutation; Oligopeptides/chemistry; Protein Binding; Protein Structure, Tertiary; Proto-Oncogene Proteins c-met/chemistry; Proto-Oncogene Proteins c-met/genetics; Proto-Oncogene Proteins c-met/metabolism; Receptor Protein-Tyrosine Kinases/antagonists & inhibitors; Receptor Protein-Tyrosine Kinases/genetics; Receptor Protein-Tyrosine Kinases/metabolism; Receptors, Neurokinin-1/genetics; Receptors, Neurokinin-1/metabolism; Recombinant Fusion Proteins/metabolism; Scattering, Radiation; X-Ray Diffraction

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:MET

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P14210

F

Seeded From UniProt

complete

HUMAN:MET

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q08048

F

Seeded From UniProt

complete

HUMAN:HGF

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P08581

F

Seeded From UniProt

complete

MOUSE:HGF

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P08581

F

Seeded From UniProt

complete

HUMAN:HGF

enables

GO:0042802: identical protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P14210

F

Seeded From UniProt

complete

Notes

See also

References

See Help:References for how to manage references in GONUTS.