Engineering the NK1 fragment of hepatocyte growth factor/scatter factor as a MET receptor antagonist |
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Authors: | Youles Mark Holmes Oliver Petoukhov Maxim V Nessen Merel A Stivala Simona Svergun Dmitri I Gherardi Ermanno |
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Institution: | 1 Medical Research Council Centre, Hills Road, Cambridge CB2 2QH, UK 2 European Molecular Biology Laboratory, Hamburg Outstation, Notkestraße 85, D-22603 Hamburg, Germany 3 Institute of Crystallography, Russian Academy of Sciences, Leninsky pr. 59, 117333 Moscow, Russia |
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Abstract: | The growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF) and its receptor MET, the tyrosine kinase encoded by the c-MET proto-oncogene, exert major roles in cancer invasion and metastasis and are key targets for therapy. NK1 is an alternative spliced variant of HGF/SF that consists of the N-terminal (N) and first kringle (K1) domains and has partial agonistic activity. NK1 crystallises as a head-to-tail dimer with an extensive inter-protomeric interface resulting from contacts between the two short interdomain linkers and reciprocal contacts between the N and K1 domains. Here we show that a subset of mutants at the NK1 dimer interface, such as the linker mutants Y124A or N127A or the kringle mutant V140A:I142A, bind the MET receptor with affinities comparable to wild-type NK1 but fail to assemble a dimeric, signalling competent NK1-MET complex. These NK1 variants have no detectable agonistic activity on, behave as bona fide receptor antagonists by blocking cell migration and DNA synthesis in target cells and have strong prospects as therapeutics for human cancer. |
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Keywords: | ERK extracellular regulated protein kinase HGF hepatocyte growth factor SF scatter factor NK1 splice variant of HGF/SF that consists of the N-terminal (N) and first kringle (K1) domains SPH serine proteinase homology SAXS small-angle X-ray scattering SPR surface plasmon resonance MDCK Madin-Darby canine kidney |
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