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Structural mechanisms of TRPV2 modulation by endogenous and exogenous ligands

Abstract

The transient receptor potential vanilloid 2 (TRPV2) ion channel is a polymodal receptor widely involved in many physiological and pathological processes. Despite many TRPV2 modulators being identified, whether and how TRPV2 is regulated by endogenous lipids remains elusive. Here, we report an endogenous cholesterol molecule inside the vanilloid binding pocket (VBP) of TRPV2, with a ‘head down, tail up’ configuration, resolved at 3.2 Å using cryo-EM. Cholesterol binding antagonizes ligand activation of TRPV2, which is removed from VBP by methyl-β-cyclodextrin (MβCD) as resolved at 2.9 Å. We also observed that estradiol (E2) potentiated TRPV2 activation by 2-aminoethoxydiphenyl borate (2-APB), a classic tool compound for TRP channels. Our cryo-EM structures (resolved at 2.8–3.3 Å) further suggest how E2 disturbed cholesterol binding and how 2-APB bound within the VBP with E2 or without both E2 and endogenous cholesterol, respectively. Therefore, our study has established the structural basis for ligand recognition of the inhibitory endogenous cholesterol and excitatory exogenous 2-APB in TRPV2.

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Fig. 1: An endogenous cholesterol binds to the VBP in TRPV2 to inhibit this channel.
Fig. 2: MβCD depletes cholesterol to remove its density from VBP and enhance 2-APB activation.
Fig. 3: The binding mechanism of cholesterol inside the VBP of TRPV2.
Fig. 4: The cholesterol derivative E2 potentiates TRPV2 activation by 2-APB.
Fig. 5: The binding mechanism of 2-APB inside the VBP.

Data availability

Structure coordinates and cryo-EM density maps have been deposited in the Protein Data Bank under accession numbers 7XEM and EMD-33156 for mTRPV2CHL, 7XEO and EMD-33157 for mTRPV2MβCD, 7XEW and EMD-33161 for mTRPV2Q525F, 7XER and EMD-33158 for mTRPV2Q525T_LMNG, 7XEU and EMD-33159 for mTRPV2E2, 7XEV and EMD-33160 for mTRPV2E2_2-APB, and 7YEP and EMD-33774 for mTRPV2MβCD_2-APB. Source data are provided with this paper.

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Acknowledgements

Single-particle cryo-EM data were collected at the Center of Cryo-Electron Microscopy at Zhejiang University. We thank X. Zhang for his support in facility access and data acquisition. We thank Y. Zhang and Y. Feng for their constructive suggestions. This work was supported in part by the National Natural Science Foundation of China (32122040 and 31971040 to F.Y.; 31870724 to J.G.; 31741067, 81630091 and 31670840 to W.Y.), the Ministry of Science and Technology (2020YFA0908501 and 2018YFA0508100 to J.G.), China Postdoctoral Science Foundation (2021M692818 to N.S.), the Fundamental Research Funds for the Central Universities (2021FZZX001-28 to J.G.) and Zhejiang Provincial Natural Science Foundation (LR20C050002 to F.Y. and LR19C050002 to J.G.). J.G. and F.Y. are supported by MOE Frontier Science Center for Brain Science & Brain–Machine Integration, Zhejiang University. This work was also supported by the Core Facilities in Zhejiang University School of Medicine, including the Zeiss LSM800 confocal fluorescence imaging microscope. F.Y. was supported by Alibaba Cloud.

Author information

Authors and Affiliations

Authors

Contributions

F.Y., J.G., W.Y. and H.W. conceived and supervised the project. N.S., W.Z, X.C., C.Z. and Y.J. undertook sample preparation, data acquisition and structure determination. W.Z and H.Z. performed the functional studies. Q.W, X.W., S.L., H.W. and F.Y. performed the MD simulation. N.S., L.X., F.Y. and J.G. undertook structural data analysis. All authors participated in the data analysis and manuscript preparation.

Corresponding authors

Correspondence to Han Wen, Wei Yang, Jiangtao Guo or Fan Yang.

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Nature Chemical Biology thanks Yifan Cheng and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Structure determination of mTRPV2CHL.

a, Size-exclusion chromatography of mTRPV2CHL on Superose 6 (GE Healthcare) and SDS-PAGE analysis of the final sample. n = 3 independent experiments. b, Representative cryo-EM micrograph of mTRPV2CHL. n = 3 independent experiments. c, Flowchart of image processing for mTRPV2CHL particles. d, Angular distribution plot of particles included in the final C4-symmetric 3D reconstruction of mTRPV2CHL. e, The density map of mTRPV2CHL colored by local resolution (Å). f, The Gold standard Fourier Shell Correlation (FSC) curve of the final 3D reconstruction of mTRPV2CHL, and the FSC curve for cross-validation between the map and the model of mTRPV2CHL. g, Sample maps of six transmembrane helices (TMs) in mTRPV2CHL. The density corresponding to cholesterol is also shown. The density is shown as a mask around each TM at the level of 0.016 in UCSF Chimera. The maps are low-pass filtered to 3.17 Å and sharpened with a B factor of –99 Å2. h, Lipid densities in mTRPV2CHL map is colored in yellow. i, Comparison of the atomic models of mTRPV2CHL and ratTRPV1 (7MZ6).

Source data

Extended Data Fig. 2 Selectivity of cholesterol inhibition.

a, Representative whole-cell recording showing the potentiation of 2-APB inhibition by CHS. b, 2-APB activation of TRPV2 channel is concentration-dependently inhibited by CHS or cholesterol in whole-cell patch-clamp recordings (n = 5 cells). Data were presented as mean ± s.e.m. c, Amino acid sequence alignment of TRPV1, TRPV2 and TRPV3 in the VBP. d, Structural alignment of TRPV1, TRPV2 and TRPV3 in the VBP. e and f, Representative current recordings of TRPV1 or TRPV3 in the whole-cell configuration, respectively. Like TRPV2, both TRPV1 and TRPV3 are activated by 2-APB. But neither TRPV1 nor TRPV3 is inhibited by cholesterol up to 250 µM. g, Representative whole-cell recording showing the potentiation of 2-APB activation by CHS on m TRPV3.

Source data

Extended Data Fig. 3 MD simulations of cholesterol binding in mTRPV2CHL.

a, RMSD of cholesterol is also plotted against simulation time in four independent all-atom MD trajectories. b, Ensemble plot of the cholesterol molecule in the VBP of TRPV2 in all-atom MD simulations.

Source data

Extended Data Fig. 4 MD simulations of cholesterol binding in mTRPV2Q525F and mTRPV2Q525T_LMNG.

a, RMSD of Q525F is also plotted against simulation time in three independent all-atom MD trajectories. b, RMSD of Q525T is also plotted against simulation time in three independent all-atom MD trajectories. c, Cholesterol inside the VBP of mTRPV2Q525T_LMNG. The residues close to cholesterol and employed to measure their distance to cholesterol are shown. d, The probability distribution of distance between cholesterol and VBP residues (measured at center of mass in Y466, L470, L477, S498 and L502).

Source data

Extended Data Fig. 5 TRPV2 inhibition by cholesterol derivatives.

a, Chemical structures of cholesterol and its derivatives dexamethasone (DEX), chorionic corticotropin (CCT) and human chorionic thyrotropin (HCT). b, representative whole-cell recording of TRPV2 current activated by 2-APB is inhibited by DEX, HCT or CCT at 30 µM. c, Percentage of TRPV2 current inhibition by 30 μM HCT, DEX, and CCT (n = 6 cells). Data were presented as mean ± s.e.m.

Source data

Extended Data Fig. 6 MD simulations of cholesterol binding in mTRPV2CHL structure with E2 added.

a, The ensemble plot of the 200 ns simulation time, E2 molecules (as denoted by its oxygen atom as a sphere in red) participated within the membrane (region shaded in grey). b, RMSD of mTRPV2CHL added E2 is also plotted against simulation time in three independent all-atom MD trajectories. c, The probability distribution of distance between cholesterol and VBP residues (measured at center of mass in Y466, L470, L477, S498 and L502).

Source data

Extended Data Fig. 7 Structure determination of mTRPV2E2_2-APB.

a, Representative cryo-EM micrograph of mTRPV2E2_2-APB. n = 3 independent experiments. b, Flowchart of image processing for mTRPV2E2_2-APB particles. c, The density map of mTRPV2E2_2-APB colored by local resolution. d, Distribution of orientations over azimuth and elevation angles for particles included in the calculation of the final map. e, Gold-standard Fourier Shell Correlation (FSC) curves calculated with different masks in cryoSPARC. f, The FSC curve for cross-validation between the map and the model of mTRPV2E2_2-APB. g, Sample maps of six transmembrane helices (TMs) in mTRPV2E2_2-APB. The density corresponding to 2-APB is also shown. The density is shown as a mask around each TM at the level of 0.006 in UCSF Chimera. The maps are low-pass filtered to 3.27 Å and sharpened with a B factor of -99.6 Å2.

Source data

Extended Data Fig. 8 TRPV2 mutants with abolished 2-APB activation are still functional.

a to d, Representative current activation by 2 mM probenecid in the mutant Y466A, Q525N, L620A and L627T, respectively, where 2-APB (2 mM) activation is virtually abolished. The protein of these mutants is expressed on the cell membrane as shown in confocal imaging. n = 3 independent experiments. e, Magnitude of current activation by probenecid (2 mM) in TRPV2 mutants (n = 3-4 cells). Data were presented as mean ± s.e.m.

Source data

Extended Data Fig. 9 The 2-APB binding site.

a to c, 3D reconstruction maps of mTRPV2E2_2-APB, 2-APB bounded inactivated state of rat TRPV2 (7N0M), and 2-APB bounded activated state of rat TRPV2 (7NON). Dashed circles in red or purple indicates the binding site of 2-APB observed in our study or in rat TRPV2 (7N0M or 7NON), respectively. d, Comparison of the atomic models of our mTRPV2CHL and rat TRPV2 (5HI9) in the apo state.

Extended Data Fig. 10 TRPV2 desensitization is accelerated by E2.

a, representative whole-cell recordings of TRPV2 activation and desensitization by 2-APB alone or with E2 (dots in green or orange, respectively) in calcium-free solution. An exponential function is fitted to the desensitization time course to determine the time constant. b, comparison of the desensitization time constant of TRPV2 by 2-APB in the presence or absence of E2 (n = 3-5 cells). Data were presented as mean ± s.e.m. Two-tailed t-test was performed. *, p = 0.0441 in t-test.

Source data

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Su, N., Zhen, W., Zhang, H. et al. Structural mechanisms of TRPV2 modulation by endogenous and exogenous ligands. Nat Chem Biol (2022). https://doi.org/10.1038/s41589-022-01139-8

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