Characterization and structural determination of a new anti-MET function-blocking antibody with binding epitope distinct from the ligand binding domain.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
AuthorsDiCara, Danielle M
Chirgadze, Dimitri Y
Pope, Anthony R
van den Heuvel, Joop
Packman, Len C
MetadataShow full item record
AbstractThe growth and motility factor Hepatocyte Growth Factor/Scatter Factor (HGF/SF) and its receptor, the product of the MET proto-oncogene, promote invasion and metastasis of tumor cells and have been considered potential targets for cancer therapy. We generated a new Met-blocking antibody which binds outside the ligand-binding site, and determined the crystal structure of the Fab in complex with its target, which identifies the binding site as the Met Ig1 domain. The antibody, 107_A07, inhibited HGF/SF-induced cell migration and proliferation in vitro and inhibited growth of tumor xenografts in vivo. In biochemical assays, 107_A07 competes with both HGF/SF and its truncated splice variant NK1 for MET binding, despite the location of the antibody epitope on a domain (Ig1) not reported to bind NK1 or HGF/SF. Overlay of the Fab-MET crystal structure with the InternalinB-MET crystal structure shows that the 107_A07 Fab comes into close proximity with the HGF/SF-binding SEMA domain when MET is in the "compact", InternalinB-bound conformation, but not when MET is in the "open" conformation. These findings provide further support for the importance of the "compact" conformation of the MET extracellular domain, and the relevance of this conformation to HGF/SF binding and signaling.
CitationCharacterization and structural determination of a new anti-MET function-blocking antibody with binding epitope distinct from the ligand binding domain. 2017, 7 (1):9000 Sci Rep
AffiliationHelmholtz-Zentrum für Infektionsforschung GmbH. Inhoffenstr. 7, 38124 Braunschweig, Germany.
The following license files are associated with this item:
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by-nc-sa/4.0/
- Structural basis of MET receptor dimerization by the bacterial invasion protein InlB and the HGF/SF splice variant NK1.
- Authors: Niemann HH
- Issue date: 2013 Oct
- Therapeutic potential of hepatocyte growth factor/scatter factor neutralizing antibodies: inhibition of tumor growth in both autocrine and paracrine hepatocyte growth factor/scatter factor:c-Met-driven models of leiomyosarcoma.
- Authors: Gao CF, Xie Q, Zhang YW, Su Y, Zhao P, Cao B, Furge K, Sun J, Rex K, Osgood T, Coxon A, Burgess TL, Vande Woude GF
- Issue date: 2009 Oct
- A functional domain in the heavy chain of scatter factor/hepatocyte growth factor binds the c-Met receptor and induces cell dissociation but not mitogenesis.
- Authors: Hartmann G, Naldini L, Weidner KM, Sachs M, Vigna E, Comoglio PM, Birchmeier W
- Issue date: 1992 Dec 1
- Molecular characteristics of HGF-SF and its role in cell motility and invasion.
- Authors: Weidner KM, Hartmann G, Naldini L, Comoglio PM, Sachs M, Fonatsch C, Rieder H, Birchmeier W
- Issue date: 1993
- Identification of functional domains in the hepatocyte growth factor and its receptor by molecular engineering.
- Authors: Bardelli A, Ponzetto C, Comoglio PM
- Issue date: 1994 Sep 30