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Heat-dependent opening of TRPV1 in the presence of capsaicin

Nature Structural & Molecular Biology volume 28, pages 554–563 (2021)Cite this article

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Abstract

Transient receptor potential vanilloid member 1 (TRPV1) is a Ca2+-permeable cation channel that serves as the primary heat and capsaicin sensor in humans. Using cryo-EM, we have determined the structures of apo and capsaicin-bound full-length rat TRPV1 reconstituted into lipid nanodiscs over a range of temperatures. This has allowed us to visualize the noxious heat-induced opening of TRPV1 in the presence of capsaicin. Notably, noxious heat-dependent TRPV1 opening comprises stepwise conformational transitions. Global conformational changes across multiple subdomains of TRPV1 are followed by the rearrangement of the outer pore, leading to gate opening. Solvent-accessible surface area analyses and functional studies suggest that a subset of residues form an interaction network that is directly involved in heat sensing. Our study provides a glimpse of the molecular principles underlying noxious physical and chemical stimuli sensing by TRPV1, which can be extended to other thermal sensing ion channels.

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Fig. 1: Structures of the full-length TRPV1 in six conditions.
Fig. 2: TRPV1 retains sensitivity to noxious heat after capsaicin sensitization and opens in a stepwise manner.
Fig. 3: Global conformational changes of the first noxious heat-induced transition.
Fig. 4: Conformational changes in the outer pore during the second transition.
Fig. 5: Conformational changes in the S6 gate during the second transition.
Fig. 6: Structure mapping of SASA-based heat capacity changes.
Fig. 7: Working model of TRPV1 heat activation.

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Data availability

The coordinates are deposited in the Protein Data Bank with PDB IDs 7LP9 (TRPV14C,APO), 7LPA (TRPV14C,CAP), 7LPB (TRPV125C,CAP), 7LPC (TRPV148C,APO), 7LPD (TRPV148C,CAP,INT) and 7LPE (TRPV148C,CAP,OPEN), respectively. The cryo-EM maps are deposited in the Electron Microscopy Data Bank with IDs EMD-23473 (TRPV14C,APO), EMD-23474 (TRPV14C,CAP), EMD-23475 (TRPV125C,CAP), EMD-23476 (TRPV148C,APO), EMD-23477 (TRPV148C,CAP,10sec), EMD-23478 (TRPV148C,CAP,INT) and EMD-23479 (TRPV148C,CAP,OPEN), respectively. Source data are provided with this paper.

References

  1. Caterina, M. J. & Julius, D. The vanilloid receptor: a molecular gateway to the pain pathway. Annu. Rev. Neurosci. 24, 487–517 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Ramsey, I. S., Delling, M. & Clapham, D. E. An introduction to TRP channels. Annu. Rev. Physiol. 68, 619–647 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Vriens, J. & Voets, T. Heat sensing involves a TRiPlet of ion channels. Br. J. Pharmacol. 176, 3893–3898 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Vay, L., Gu, C. & McNaughton, P. A. The thermo-TRP ion channel family: properties and therapeutic implications. Br. J. Pharmacol. 165, 787–801 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bandell, M., Macpherson, L. J. & Patapoutian, A. From chills to chilis: mechanisms for thermosensation and chemesthesis via thermo TRPs. Curr. Opin. Neurobiol. 17, 490–497 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Caterina, M. J. et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389, 816–824 (1997).

    Article  CAS  PubMed  Google Scholar 

  7. Szallasi, A. et al. Resiniferatoxin-type phorboid vanilloids display capsaicin-like selectivity at native vanilloid receptors on rat DRG neurons and at the cloned vanilloid receptor VR1. Br. J. Pharmacol. 128, 428–434 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Voets, T. et al. The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels. Nature 430, 748–754 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Brauchi, S., Orio, P. & Latorre, R. Clues to understanding cold sensation: thermodynamics and electrophysiological analysis of the cold receptor TRPM8. Proc. Natl Acad. Sci. USA 101, 15494–15499 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yin, Y. et al. Structure of the cold- and menthol-sensing ion channel TRPM8. Science 359, 237–241 (2018).

    Article  CAS  PubMed  Google Scholar 

  11. Yang, S. et al. A paradigm of thermal adaptation in penguins and elephants by tuning cold activation in TRPM8. Proc. Natl Acad. Sci. USA 117, 8633–8638 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Paricio-Montesinos, R. et al. The sensory coding of warm perception. Neuron 106, 830–841 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yao, J., Liu, B. & Qin, F. Kinetic and energetic analysis of thermally activated TRPV1 channels. Biophys. J. 99, 1743–1753 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Grandl, J. et al. Temperature-induced opening of TRPV1 ion channel is stabilized by the pore domain. Nat. Neurosci. 13, 708–714 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kim, S. E., Patapoutian, A. & Grandl, J. Single residues in the outer pore of TRPV1 and TRPV3 have temperature-dependent conformations. PLoS ONE 8, e59593 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yao, J., Liu, B. & Qin, F. Modular thermal sensors in temperature-gated transient receptor potential (TRP) channels. Proc. Natl Acad. Sci. USA 108, 11109–11114 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Jara-Oseguera, A., Bae, C. & Swartz, K. J. An external sodium ion binding site controls allosteric gating in TRPV1 channels. Elife 5, e13356 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Zhang, F. et al. Heat activation is intrinsic to the pore domain of TRPV1. Proc. Natl Acad. Sci. USA 115, E317–E324 (2018).

    CAS  PubMed  Google Scholar 

  19. Vlachova, V. et al. Functional role of C-terminal cytoplasmic tail of rat vanilloid receptor 1. J. Neurosci. 23, 1340–1350 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yang, F., Cui, Y., Wang, K. & Zheng, J. Thermosensitive TRP channel pore turret is part of the temperature activation pathway. Proc. Natl Acad. Sci. USA 107, 7083–7088 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kim, M. et al. Evidence that the TRPV1 S1–S4 membrane domain contributes to thermosensing. Nat. Commun. 11, 4169 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Clapham, D. E. & Miller, C. A thermodynamic framework for understanding temperature sensing by transient receptor potential (TRP) channels. Proc. Natl Acad. Sci. USA 108, 19492–19497 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chowdhury, S., Jarecki, B. W. & Chanda, B. A molecular framework for temperature-dependent gating of ion channels. Cell 158, 1148–1158 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Jordt, S. E. & Julius, D. Molecular basis for species-specific sensitivity to ‘hot’ chili peppers. Cell 108, 421–430 (2002).

    Article  CAS  PubMed  Google Scholar 

  25. Cao, E., Liao, M., Cheng, Y. & Julius, D. TRPV1 structures in distinct conformations reveal activation mechanisms. Nature 504, 113–118 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gao, Y., Cao, E., Julius, D. & Cheng, Y. TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action. Nature 534, 347–351 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Liao, M., Cao, E., Julius, D. & Cheng, Y. Structure of the TRPV1 ion channel determined by electron cryo-microscopy. Nature 504, 107–112 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yang, F. et al. Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel. Nat. Chem. Biol. 11, 518–524 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Elokely, K. et al. Understanding TRPV1 activation by ligands: insights from the binding modes of capsaicin and resiniferatoxin. Proc. Natl Acad. Sci. USA 113, E137–E145 (2016).

    Article  CAS  PubMed  Google Scholar 

  30. Darre, L. & Domene, C. Binding of capsaicin to the TRPV1 ion channel. Mol. Pharm. 12, 4454–4465 (2015).

    Article  CAS  PubMed  Google Scholar 

  31. Hanson, S. M., Newstead, S., Swartz, K. J. & Sansom, M. S. P. Capsaicin interaction with TRPV1 channels in a lipid bilayer: molecular dynamics simulation. Biophys. J. 108, 1425–1434 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Smart, O. S., Neduvelil, J. G., Wang, X., Wallace, B. A. & Sansom, M. S. HOLE: a program for the analysis of the pore dimensions of ion channel structural models. J. Mol. Graph. 14, 354–360 (1996).

    Article  CAS  PubMed  Google Scholar 

  33. Nadezhdin, K. D. et al. Extracellular cap domain is an essential component of the TRPV1 gating mechanism. Nat. Commun. 12, 2154 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Jordt, S. E., Tominaga, M. & Julius, D. Acid potentiation of the capsaicin receptor determined by a key extracellular site. Proc. Natl Acad. Sci. USA 97, 8134–8139 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zubcevic, L., Borschel, W. F., Hsu, A. L., Borgnia, M. J. & Lee, S. Y. Regulatory switch at the cytoplasmic interface controls TRPV channel gating. Elife 8, e47746 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Singh, A. K. et al. Structural basis of temperature sensation by the TRP channel TRPV3. Nat. Struct. Mol. Biol. 26, 994–998 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Swain, J. & Kumar Mishra, A. Location, partitioning behavior and interaction of capsaicin with lipid bilayer membrane: study using its intrinsic fluorescence. J. Phys. Chem. B 119, 12086–12093 (2015).

    Article  CAS  PubMed  Google Scholar 

  38. Sánchez-Moreno, A. et al. Irreversible temperature gating in trpv1 sheds light on channel activation. Elife 7, e36372 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Ladrón-de-Guevara, E. et al. The contribution of the ankyrin repeat domain of TRPV1 as a thermal module. Biophys. J. 118, 836–845 (2020).

    Article  PubMed  CAS  Google Scholar 

  40. Ryu, S., Liu, B., Yao, J., Fu, Q. & Qin, F. Uncoupling proton activation of vanilloid receptor TRPV1. J. Neurosci. 27, 12797–12807 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bae, C. et al. Structural insights into the mechanism of activation of the TRPV1 channel by a membrane-bound tarantula toxin. Elife 5, e11273 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Salazar, H. et al. Structural determinants of gating in the TRPV1 channel. Nat. Struct. Mol. Biol. 16, 704–710 (2009).

    Article  CAS  PubMed  Google Scholar 

  43. Steinberg, X. et al. Conformational dynamics in TRPV1 channels reported by an encoded coumarin amino acid. Elife 6, e28626 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Zubcevic, L. & Lee, S. Y. The role of π-helices in TRP channel gating. Curr. Opin. Struct. Biol. 58, 314–323 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Susankova, K., Ettrich, R., Vyklicky, L., Teisinger, J. & Vlachova, V. Contribution of the putative inner-pore region to the gating of the transient receptor potential vanilloid subtype 1 channel (TRPV1). J. Neurosci. 27, 7578–7585 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Makhatadze, G. I. & Privalov, P. L. Energetics of protein structure. Adv. Protein Chem. 47, 307–425 (1995).

    Article  CAS  PubMed  Google Scholar 

  47. Henriques, D. A., Ladbury, J. E. & Jackson, R. M. Comparison of binding energies of SrcSH2-phosphotyrosyl peptides with structure-based prediction using surface area based empirical parameterization. Protein Sci. 9, 1975–1985 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Franzese, G. & Rubi, M. (eds) Aspects of Physical Biology: Biological Water, Protein Solutions, Transport and Replication (Springer, 2008).

  49. Voets, T. Quantifying and modeling the temperature-dependent gating of TRP channels. Rev. Physiol. Biochem. Pharmacol. 162, 91–119 (2012).

    CAS  PubMed  Google Scholar 

  50. Chen, H., Deng, J., Cui, Q., Chanda, B. & Henzler-Wildman, K. Mapping temperature-dependent conformational change in the voltage-sensing domain of an engineered heat-activated K+ channel. Proc. Natl Acad. Sci. USA 118, e2017280118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Goehring, A. et al. Screening and large-scale expression of membrane proteins in mammalian cells for structural studies. Nat. Protoc. 9, 2574–2585 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ritchie, T. K. et al. Chapter 11—Reconstitution of membrane proteins in phospholipid bilayer nanodiscs. Methods Enzymol. 464, 211–231 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zheng, S. Q. et al. MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy. Nat. Methods 14, 331–332 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zhang, K. Gctf: real-time CTF determination and correction. J. Struct. Biol. 193, 1–12 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zivanov, J. et al. New tools for automated high-resolution cryo-EM structure determination in RELION-3. Elife 7, e42166 (2018).

  56. Punjani, A., Rubinstein, J. L., Fleet, D. J. & Brubaker, M. A. cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat. Methods 14, 290–296 (2017).

    Article  CAS  PubMed  Google Scholar 

  57. Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D Biol. Crystallogr. 60, 2126–2132 (2004).

    Article  PubMed  CAS  Google Scholar 

  58. Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D Biol. Crystallogr. 66, 213–221 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Chen, V. B. et al. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr. D Biol. Crystallogr. 66, 12–21 (2010).

    Article  CAS  PubMed  Google Scholar 

  60. Delano, W. L. The PyMol Molecular Graphics System (DeLano Scientific, 2002).

    Google Scholar 

  61. Goddard, T. D., Huang, C. C. & Ferrin, T. E. Visualizing density maps with UCSF Chimera. J. Struct. Biol. 157, 281–287 (2007).

    Article  CAS  PubMed  Google Scholar 

  62. Kang, K. et al. Modulation of TRPA1 thermal sensitivity enables sensory discrimination in Drosophila. Nature 481, 76–80 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Fraczkiewicz, R. & Braun, W. Exact and efficient analytical calculation of the accessible surface areas and their gradients for macromolecules. J. Comput. Chem. 19, 319–333 (1998).

    Article  CAS  Google Scholar 

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Acknowledgements

Cryo-EM data were collected at the Duke University Shared Materials Instrumentation Facility (SMIF) and at the Pacific Northwest Center for Cryo-EM (PNCC) at OHSU. We thank J. Myers at PNCC for assistance with data collection, N. Bhattacharya at SMIF for assistance with the microscope operation, L.B. Dillard at NIEHS for assistance with sample screening, and A. Bartesaghi at Duke for a pre-processing interface for data collection. We thank J. Fedor and Y. Yin for critical reading of the manuscript and discussions, W. Borschel for training F. Zhang on the patch-clamp recording, J. Grandl for discussions and W. Im for advice on the solvent accessibility analysis. This research was supported by NIH grant R35NS097241 (to S.-Y.L.) and by the National Institute of Health Intramural Research Program, US National Institutes of Environmental Health Sciences (ZIC ES103326 to M.J.B). A portion of this research was supported by NIH grant U24GM129547 and performed at the PNCC at OHSU and accessed through EMSL (grid.436923.9), a DOE Office of Science User Facility sponsored by the Office of Biological and Environmental Research. DUKE SMIF is affiliated with the North Carolina Research Triangle Nanotechnology Network, which is in part supported by the NSF (ECCS-2025064).

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Authors and Affiliations

  1. Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA

    Do Hoon Kwon, Feng Zhang, Yang Suo & Seok-Yong Lee

  2. Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, USA

    Jonathan Bouvette & Mario J. Borgnia

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Contributions

D.H.K. conducted biochemical preparation, sample freezing and single-particle 3D reconstruction under the guidance of S.-Y.L. F.Z. carried out all electrophysiological recordings under the guidance of S.-Y.L. Y.S. collected cryo-EM data and helped D.H.K. with cryo-EM data processing. D.H.K. and S.-Y.L. performed model building. J.B. helped D.H.K. in part of the sample screening under the guidance of M.J.B. S.-Y.L. and D.H.K. wrote the manuscript.

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Correspondence to Seok-Yong Lee.

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The authors declare no competing interests.

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Peer review information Nature Structural & Molecular Biology thanks Chia-Hsueh Lee and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available. Florian Ullrich was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 TRPV1 data collection and processing.

Data processing procedures, a, Data processing flow chart for TRPV14C,APO, TRPV14C,CAP, TRPV125C,CAP, TRPV148C,APO. b, representative micrographs, see Table 1 for details. c, 2D classification images, d, 3D reconstructions, e, local resolution estimation, f, the Euler distribution plot, g, FSC curves for TRPV14C,APO, TRPV14C,CAP, TRPV125C,CAP, TRPV148C,APO, TRPV148C,CAP,OPEN and TRPV148C,CAP,INT, respectively. h, Data processing flow chart for TRPV148C,CAP,INT and TRPV148C,CAP,OPEN.

Extended Data Fig. 2 Representative Cryo-EM density of the TRPV1 structures.

a-f, cryo-EM density for subdomains in TRPV14C,APO (a, thresholding 0.014), TRPV14C,CAP (b, thresholding 0.014), TRPV125C,CAP (c, thresholding 0.025), TRPV148C,APO (d, thresholding 0.019), TRPV148C,CAP,INT (e, thresholding 0.28), TRPV148C,CAP,OPEN (f, thresholding 0.3). Structural elements are shown as sticks and EM density as gray mesh.

Extended Data Fig. 3 Structural features of the full-length TRPV1.

a, Architecture of the TRPV1 protomer with subdomains indicated: ankyrin repeat domain (ARD), coupling domain (CD), transmembrane helices S1-S6, TRP helix, and C-terminal domain (CTD). b, Cryo-EM density (half-map without symmetry) for the selectivity filter of TRPV14C,APO corresponding to putative sodium ions at 0.04 thresholding. c, Cryo-EM density of the turret and turret junction (0.012 thresholding). d, Close-up view of the outer pore and turret junction (0.012 thresholding). e, Interaction networks spanning the outer pore region and the S1-S4 domain (0.03 thresholding). Key residues interacting with E600 and E648 are shown as sticks with surrounding cryo-EM density. f, g, Cryo-EM density of the CD, TRP, ARD (f), and CTD (g). The ARD is colored in gold, the CD and its individual elements (HTHCD, βCD,) in sky blue, the TRP domain in dark green, and the CTD in orange. The cryo-EM density (gray) is shown at 0.012 thresholding. h, Superposition of a single protomer from TRPV14C,APO (blue) and TRPV148C,APO (gold). i, Superposition of a single protomer from TRPV14C,APO (blue) and TRPV14C,CAP (cyan).

Extended Data Fig. 4 Comparison of TRPV14C,APO and TRPV148C,APO.

a, b, Cryo-EM 3D reconstructions of TRPV14C,APO (a, blue) and TRPV148C,APO (b, gold), respectively. Outlines indicate AR1-AR4. c, Close-up comparison of the cytoplasmic domains between TRPV14C,APO (blue) and TRPV148C,APO (gold).

Extended Data Fig. 5 Comparison of TRPV14C,APO, TRPV14C,CAP, TRPV125C,CAP and the published structure of TRPV1 in the presence of capsaicin.

a, Close-up view of the S1-S4 domain of TRPV14C,APO (blue) and TRPV14C,CAP (cyan). Capsaicin (red) and phosphatidyl inositol (blue) molecules are shown as sticks. b, Close-up view of capsaicin in the vanilloid pocket of TRPV14C,CAP. The cryo-EM density is shown at 0.025 thresholding. c, Side view comparison of TRPV14C,CAP (cyan) and TRPV125C,CAP (green). d, Side view comparison of TRPV14C,CAP (green) and the published TRPV1 structure in the presence of capsaicin (PDB ID: 3J5R, brown).

Extended Data Fig. 6 Comparison between the overall structures of TRPV14C,APO, TRPV148C,CAP,OPEN and DkTx/RTx-bound TRPV1.

a, Comparison of TRPV14C,APO (silver), TRPV148C,CAP,OPEN (red), and DkTx/RTx-TRPV1 (blue) viewed from the intracellular side. ARD/CD movement occurs at an individual protomer level. b, Comparison of the S6b and TRP domain of TRPV14C,APO, TRPV148C,CAP,OPEN, and DkTx/RTx-TRPV1. c, Close-up view of TRPV14C,APO, TRPV148C,CAP,OPEN, and DkTx/RTx-TRPV1 in the cytoplasmic domains. d, Alternate angle and close-up view of TRPV14C,APO, TRPV148C,CAP,OPEN, and DkTx/RTx-TRPV1 in the cytoplasmic domains.

Extended Data Fig. 7 Comparison of TRPV148C,CAP,OPEN and DkTx/RTx-bound TRPV1 structures.

a, The overlapping locations of phospholipid (TRPV148C,CAP,OPEN, red) and DkTx (DkTx/RTx-TRPV1, blue), shown as sticks and spheres, between the pore loop and pore helix. Several side chains are shown as sticks to illustrate the differences in the outer pore of the two structures. b, Structural differences between TRPV148C,CAP,OPEN and DkTx/RTx-TRPV1 at S6, the S4-S5 linker, and the TRP helix.

Extended Data Fig. 8 Solvent accessible surface area-based heat capacity change plots for the first and the second transitions.

a, b, ΔCPpred plots for the first (a) and second (b) transitions. For each transition, residues exhibiting positive ΔCPpred are plotted in the upper graph using log10(ΔCPpred), and residues exhibiting negative ΔCPpred are plotted in the lower graph using -log10(-ΔCPpred). The dotted line denotes the 15 J mol-1 K-1 threshold. ΔCPpred was calculated as described in the Methods. Residues for which the side chains were not resolved were not included in the calculation.

Extended Data Fig. 9 Rearrangement in the vanilloid pocket during the heat-dependent transitions.

a, Close-up view of the vanilloid binding site in TRPV125C,CAP (green), TRPV148C,CAP,INT (orange), and TRPV148C,CAP,OPEN (red). Several key residues in capsaicin are shown as sticks. Dotted lines denote either H-bond or salt bridge interactions. The 310 helical region of S4 is indicated as 310. b, Close-up view of S5 and S6 in TRPV148C,CAP,INT (orange), and TRPV148C,CAP,OPEN (red). The π helical turn in S6 is denoted by π. c, Comparison of TRPV148C,CAP,OPEN (red) and DkTx/RTx-bound TRPV1 (PDB ID: 5IRX, blue). DkTx is shown as sticks and gray spheres; capsaicin is depicted as sticks only.

Supplementary information

Source data

Source Data Fig. 2

Statistical source data for the electrophysiology experiment.

Source Data Fig. 5

Statistical source data for the electrophysiology experiment.

Source Data Fig. 6

Statistical source data for the electrophysiology experiment.

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Kwon, D.H., Zhang, F., Suo, Y. et al. Heat-dependent opening of TRPV1 in the presence of capsaicin. Nat Struct Mol Biol 28, 554–563 (2021). https://doi.org/10.1038/s41594-021-00616-3

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