7MO7

Cryo-EM structure of 2:2 c-MET/HGF holo-complex

Summary for 7MO7

• Entry DOI: 10.2210/pdb7mo7/pdb
• EMDB information: 23919
• Descriptor: Hepatocyte growth factor, Hepatocyte growth factor receptor, 2-O-sulfo-alpha-L-idopyranuronic acid-(1-4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose-(1-4)-2-O-sulfo-alpha-L-idopyranuronic acid-(1-4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose-(1-4)-2-O-sulfo-alpha-L-idopyranuronic acid-(1-4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose (3 entities in total)
• Functional Keywords: c-met, hgf, receptor tyrosine kinase, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 479691.33

Authors

Uchikawa, E.,Chen, Z.M.,Xiao, G.Y.,Zhang, X.W.,Bai, X.C. (deposition date: 2021-05-01, release date: 2021-06-09, Last modification date: 2021-07-28)

Primary citation

Uchikawa, E.,Chen, Z.,Xiao, G.Y.,Zhang, X.,Bai, X.C.
Structural basis of the activation of c-MET receptor.
Nat Commun, 12:4074-4074, 2021

PubMed Abstract: The c-MET receptor is a receptor tyrosine kinase (RTK) that plays essential roles in normal cell development and motility. Aberrant activation of c-MET can lead to both tumors growth and metastatic progression of cancer cells. C-MET can be activated by either hepatocyte growth factor (HGF), or its natural isoform NK1. Here, we report the cryo-EM structures of c-MET/HGF and c-MET/NK1 complexes in the active state. The c-MET/HGF complex structure reveals that, by utilizing two distinct interfaces, one HGF molecule is sufficient to induce a specific dimerization mode of c-MET for receptor activation. The binding of heparin as well as a second HGF to the 2:1 c-MET:HGF complex further stabilize this active conformation. Distinct to HGF, NK1 forms a stable dimer, and bridges two c-METs in a symmetrical manner for activation. Collectively, our studies provide structural insights into the activation mechanisms of c-MET, and reveal how two isoforms of the same ligand use dramatically different mechanisms to activate the receptor.

PubMed: 34210960
DOI: 10.1038/s41467-021-24367-3

Experimental method

ELECTRON MICROSCOPY (4.8 Å)