期刊
NATURE CHEMICAL BIOLOGY
卷 15, 期 6, 页码 598-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41589-019-0285-7
关键词
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资金
- World Premier International Research Center Initiative (WPI), MEXT, Japan
- A-STEP (Adaptable and Seamless Technology Transfer Program through Target-driven R&D) from the Japan Science and Technology Agency (JST) [AS262Z]
- Medical Research Fund of Takeda Science Foundation
- Mitani Foundation for Research and Development
- Japan Agency for Medical Research and development (AMED)
- AMED
- Institute for Protein Research, Osaka University [CR15-05]
- Cancer Research Institute (Kanazawa University)
- [16K08544]
- [15K14473]
- [16H06830]
- [23-7727]
- [18K01836]
Activation of hepatocyte growth factor (HGF) by proteolytic processing is triggered in cancer microenvironments, and subsequent signaling through the MET receptor is involved in cancer progression. However, the structure of HGF remains elusive, and few small/medium-sized molecules can modulate HGF. Here, we identified HiP-8, a macrocyclic peptide consisting of 12 amino acids, which selectively recognizes active HGF. Biochemical analysis and real-time single-molecule imaging by high-speed atomic force microscopy demonstrated that HiP-8 restricted the dynamic domains of HGF into static closed conformations, resulting in allosteric inhibition. Positron emission tomography using HiP-8 as a radiotracer enabled noninvasive visualization and simultaneous inhibition of HGF-MET activation status in tumors in a mouse model. Our results illustrate the conformational change in proteolytic activation of HGF and its detection and inhibition by a macrocyclic peptide, which may be useful for diagnosis and treatment of cancers.
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