6GCU

MET receptor in complex with InlB internalin domain and DARPin A3A

Summary for 6GCU

• Entry DOI: 10.2210/pdb6gcu/pdb
• Descriptor: Hepatocyte growth factor receptor, Internalin B, DARPin A3A (3 entities in total)
• Functional Keywords: receptor tyrosine kinase, bacterial invasion protein, artificial binding protein, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 265413.05

Authors

Meyer, T.,Andres, F.,Iamele, L.,Gherardi, E.,Pluckthun, A.,Niemann, H.H. (deposition date: 2018-04-19, release date: 2019-05-15, Last modification date: 2024-10-09)

Primary citation

Andres, F.,Iamele, L.,Meyer, T.,Stuber, J.C.,Kast, F.,Gherardi, E.,Niemann, H.H.,Pluckthun, A.
Inhibition of the MET Kinase Activity and Cell Growth in MET-Addicted Cancer Cells by Bi-Paratopic Linking.
J.Mol.Biol., 431:2020-2039, 2019

PubMed Abstract: MET, the product of the c-MET proto-oncogene, and its ligand hepatocyte growth factor/scatter factor (HGF/SF) control survival, proliferation and migration during development and tissue regeneration. HGF/SF-MET signaling is equally crucial for growth and metastasis of a variety of human tumors, but resistance to small-molecule inhibitors of MET kinase develops rapidly and therapeutic antibody targeting remains challenging. We made use of the designed ankyrin repeat protein (DARPin) technology to develop an alternative approach for inhibiting MET. We generated a collection of MET-binding DARPins covering epitopes in the extracellular MET domains and created comprehensive sets of bi-paratopic fusion proteins. This new class of molecules efficiently inhibited MET kinase activity and downstream signaling, caused receptor downregulation and strongly inhibited the proliferation of MET-dependent gastric carcinoma cells carrying MET locus amplifications. MET-specific bi-paratopic DARPins may represent a novel and potent strategy for therapeutic targeting of MET and other receptors, and this study has elucidated their mode of action.

PubMed: 30930049
DOI: 10.1016/j.jmb.2019.03.024

Experimental method

X-RAY DIFFRACTION (6.001 Å)