ArticleThe EMBO journal2001
Crystal structures of NK1-heparin complexes reveal the basis for NK1 activity and enable engineering of potent agonists of the MET receptor.
Article in The EMBO journal, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 111 citations in OpenAlex.
- Targeting heparan sulfate-protein interactions with oligosaccharides and monoclonal antibodies.Frontiers in molecular biosciences · 2023Review
- Dimerization of kringle 1 domain from hepatocyte growth factor/scatter factor provides a potent MET receptor agonist.Life science alliance · 2022Article
- 3-Computational and structural biotechnology journal · 2022Article
- A single injection of CM1021, a long half-life hepatocyte growth factor mimetic, increases liver mass in mice.Biochemistry and biophysics reports · 2021Article
- Structural basis of the activation of c-MET receptor.Nature communications · 2021Article
- State of the structure address on MET receptor activation by HGF.Biochemical Society transactions · 2021Review
- High resolution structure of human apolipoprotein (a) kringle IV type 2: beyond the lysine binding site.Journal of lipid research · 2020Article
- A Novel HGF/SF Receptor (MET) Agonist Transiently Delays the Disease Progression in an Amyotrophic Lateral Sclerosis Mouse Model by Promoting Neuronal Survival and Dampening the Immune Dysregulation.International journal of molecular sciences · 2020Article
- Exploring the chemical space of the lysine-binding pocket of the first kringle domain of hepatocyte growth factor/scatter factor (HGF/SF) yields a new class of inhibitors of HGF/SF-MET binding.Chemical science · 2015Article
- Achieving high signal-to-noise in cell regulatory systems: Spatial organization of multiprotein transmembrane assemblies of FGFR and MET receptors.Progress in biophysics and molecular biology · 2015Review
- Fell-Muir Lecture: Heparan sulphate and the art of cell regulation: a polymer chain conducts the protein orchestra.International journal of experimental pathology · 2015Article
- Semi-synthesis of a HGF/SF kringle one (K1) domain scaffold generates a potentChemical science · 2015Article
- An engineered dimeric fragment of hepatocyte growth factor is a potent c-MET agonist.FEBS letters · 2014Article
- BFMP: a method for discretizing and visualizing pyranose conformations.Journal of chemical information and modeling · 2014Article
- Docking server for the identification of heparin binding sites on proteins.Journal of chemical information and modeling · 2014Article
- Thiocarbamate-linked polysulfonate-peptide conjugates as selective hepatocyte growth factor receptor binders.Bioconjugate chemistry · 2014Article
- Demystifying heparan sulfate-protein interactions.Annual review of biochemistry · 2014Review
- MET: a critical player in tumorigenesis and therapeutic target.Cold Spring Harbor perspectives in biology · 2013Review
- Targeted disruption of heparan sulfate interaction with hepatocyte and vascular endothelial growth factors blocks normal and oncogenic signaling.Cancer cell · 2012Article
- Galactose recognition by the apicomplexan parasite Toxoplasma gondii.The Journal of biological chemistry · 2012Article
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Authors and funding
5 authors.
Funding
Abstract
NK1 is a splice variant of the polypeptide growth factor HGF/SF, which consists of the N-terminal (N) and first kringle (K) domain and requires heparan sulfate or soluble heparin for activity. We describe two X-ray crystal structures of NK1-heparin complexes that define a heparin-binding site in the N domain, in which a major role is played by R73, with further contributions from main chain atoms of T61, K63 and G79 and the side chains of K60, T61, R76, K62 and K58. Mutagenesis experiments demonstrate that heparin binding to this site is essential for dimerization in solution and biological activity of NK1. Heparin also comes into contact with a patch of positively charged residues (K132, R134, K170 and R181) in the K domain. Mutation of these residues yields NK1 variants with increased biological activity. Thus, we uncover a complex role for heparan sulfate in which binding to the primary site in the N domain is essential for biological activity whereas binding to the K domain reduces activity. We exploit the interaction between heparin and the K domain site in order to engineer NK1 as a potent receptor agonist and suggest that dual (positive and negative) control may be a general mechanism of heparan sulfate-dependent regulation of growth factor activity.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.