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TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action

Author

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  • Yuan Gao

    (University of California
    University of California)

  • Erhu Cao

    (University of California
    †Present address: Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah 84112-5650, USA.)

  • David Julius

    (University of California)

  • Yifan Cheng

    (University of California
    Howard Hughes Medical Institute, University of California)

Abstract

When integral membrane proteins are visualized in detergents or other artificial systems, an important layer of information is lost regarding lipid interactions and their effects on protein structure. This is especially relevant to proteins for which lipids have both structural and regulatory roles. Here we demonstrate the power of combining electron cryo-microscopy with lipid nanodisc technology to ascertain the structure of the rat TRPV1 ion channel in a native bilayer environment. Using this approach, we determined the locations of annular and regulatory lipids and showed that specific phospholipid interactions enhance binding of a spider toxin to TRPV1 through formation of a tripartite complex. Furthermore, phosphatidylinositol lipids occupy the binding site for capsaicin and other vanilloid ligands, suggesting a mechanism whereby chemical or thermal stimuli elicit channel activation by promoting the release of bioactive lipids from a critical allosteric regulatory site.

Suggested Citation

  • Yuan Gao & Erhu Cao & David Julius & Yifan Cheng, 2016. "TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action," Nature, Nature, vol. 534(7607), pages 347-351, June.
    • Handle: RePEc:nat:nature:v:534:y:2016:i:7607:d:10.1038_nature17964
    DOI: 10.1038/nature17964
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    Cited by:

    1. Kaihua Zhang & Hao Wu & Nicholas Hoppe & Aashish Manglik & Yifan Cheng, 2022. "Fusion protein strategies for cryo-EM study of G protein-coupled receptors," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Junping Fan & Han Ke & Jing Lei & Jin Wang & Makoto Tominaga & Xiaoguang Lei, 2024. "Structural basis of TRPV1 inhibition by SAF312 and cholesterol," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    3. Mingxing Wang & Jin He & Shanshan Li & Qianwen Cai & Kaiming Zhang & Ji She, 2023. "Structural basis of vitamin C recognition and transport by mammalian SVCT1 transporter," Nature Communications, Nature, vol. 14(1), pages 1-8, December.
    4. Jingjing Hong & Tingting Li & Yulin Chao & Yidan Xu & Zhini Zhu & Zixuan Zhou & Weijie Gu & Qianhui Qu & Dianfan Li, 2024. "Molecular basis of the inositol deacylase PGAP1 involved in quality control of GPI-AP biogenesis," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    5. Do Hoon Kwon & Feng Zhang & Justin G. Fedor & Yang Suo & Seok-Yong Lee, 2022. "Vanilloid-dependent TRPV1 opening trajectory from cryoEM ensemble analysis," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    6. Shengjie Feng & Cristina Puchades & Juyeon Ko & Hao Wu & Yifei Chen & Eric E. Figueroa & Shuo Gu & Tina W. Han & Brandon Ho & Tong Cheng & Junrui Li & Brian Shoichet & Yuh Nung Jan & Yifan Cheng & Lil, 2023. "Identification of a drug binding pocket in TMEM16F calcium-activated ion channel and lipid scramblase," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    7. Arthur Neuberger & Kirill D. Nadezhdin & Alexander I. Sobolevsky, 2021. "Structural mechanisms of TRPV6 inhibition by ruthenium red and econazole," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    8. Lavanya Moparthi & Viktor Sinica & Vamsi K. Moparthi & Mohamed Kreir & Thibaut Vignane & Milos R. Filipovic & Viktorie Vlachova & Peter M. Zygmunt, 2022. "The human TRPA1 intrinsic cold and heat sensitivity involves separate channel structures beyond the N-ARD domain," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    9. Arthur Neuberger & Mai Oda & Yury A. Nikolaev & Kirill D. Nadezhdin & Elena O. Gracheva & Sviatoslav N. Bagriantsev & Alexander I. Sobolevsky, 2023. "Human TRPV1 structure and inhibition by the analgesic SB-366791," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    10. Liying Zhang & Charlotte Simonsen & Lucie Zimova & Kaituo Wang & Lavanya Moparthi & Rachelle Gaudet & Maria Ekoff & Gunnar Nilsson & Ute A. Hellmich & Viktorie Vlachova & Pontus Gourdon & Peter M. Zyg, 2022. "Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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