Structural basis of the activation of c-MET receptor

Emiko Uchikawa, Zhiming Chen, Guan Yu Xiao, Xuewu Zhang, Xiao chen Bai

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


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.

Original languageEnglish
Article number4074
JournalNature Communications
Issue number1
StatePublished - Dec 1 2021

Bibliographical note

Funding Information:
Cryo-EM data were collected at the University of Texas Southwestern Medical Center (UTSW) Cryo-Electron Microscopy Facility, funded in part by the Cancer Prevention and Research Institute of Texas (CPRIT) Core Facility Support Award RP170644. We thank Dr. Stoddard for facility access. This work is supported in part by grants from the National Institutes of Health (R35GM130289 to X.Z and R01GM143158 to X.-C.B.), the Welch Foundation (I-1702 to X.Z. and I-1944 to X.-C.B.), and CPRIT (RP160082 to X.-C.B.). X.-C.B. and X.Z. are Virginia Murchison Linthicum Scholars in Medical Research at UTSW. Z.C. is supported by a grant from the National Institutes of Health (GM73165 to Marcel B. Mettlen).

Publisher Copyright:
© 2021, The Author(s).

ASJC Scopus subject areas

  • Chemistry (all)
  • Biochemistry, Genetics and Molecular Biology (all)
  • Physics and Astronomy (all)


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