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Structural basis of TRPV5 channel inhibition by econazole revealed by cryo-EM.

Hughes TET, Lodowski DT, Huynh KW, Yazici A, Del Rosario J, Kapoor A, Basak S, Samanta A, Han X, Chakrapani S, Zhou ZH, Filizola M, Rohacs T, Han S, Moiseenkova-Bell VY
Nat Struct Mol Biol 25 53-60 (2018)
Cited: 73 times
EuropePMC logo PMID: 29323279

Abstract

The transient receptor potential vanilloid 5 (TRPV5) channel is a member of the transient receptor potential (TRP) channel family, which is highly selective for Ca2+, that is present primarily at the apical membrane of distal tubule epithelial cells in the kidney and plays a key role in Ca2+ reabsorption. Here we present the structure of the full-length rabbit TRPV5 channel as determined using cryo-EM in complex with its inhibitor econazole. This structure reveals that econazole resides in a hydrophobic pocket analogous to that occupied by phosphatidylinositides and vanilloids in TRPV1, thus suggesting conserved mechanisms for ligand recognition and lipid binding among TRPV channels. The econazole-bound TRPV5 structure adopts a closed conformation with a distinct lower gate that occludes Ca2+ permeation through the channel. Structural comparisons between TRPV5 and other TRPV channels, complemented with molecular dynamics (MD) simulations of the econazole-bound TRPV5 structure, allowed us to gain mechanistic insight into TRPV5 channel inhibition by small molecules.

Reviews - 6b5v mentioned but not cited (3)

  1. Structural insights into the gating mechanisms of TRPV channels. Pumroy RA, Fluck EC, Ahmed T, Moiseenkova-Bell VY. Cell Calcium 87 102168 (2020)
  2. Structural Pharmacology of TRP Channels. Zhao Y, McVeigh BM, Moiseenkova-Bell VY. J Mol Biol 433 166914 (2021)
  3. Ligand-Binding Sites in Vanilloid-Subtype TRP Channels. Yelshanskaya MV, Sobolevsky AI. Front Pharmacol 13 900623 (2022)

Articles - 6b5v mentioned but not cited (9)

  1. Structural insights on TRPV5 gating by endogenous modulators. Hughes TET, Pumroy RA, Yazici AT, Kasimova MA, Fluck EC, Huynh KW, Samanta A, Molugu SK, Zhou ZH, Carnevale V, Rohacs T, Moiseenkova-Bell VY. Nat Commun 9 4198 (2018)
  2. Structural basis of TRPV5 channel inhibition by econazole revealed by cryo-EM. Hughes TET, Lodowski DT, Huynh KW, Yazici A, Del Rosario J, Kapoor A, Basak S, Samanta A, Han X, Chakrapani S, Zhou ZH, Filizola M, Rohacs T, Han S, Moiseenkova-Bell VY. Nat Struct Mol Biol 25 53-60 (2018)
  3. A hypothetical molecular mechanism for TRPV1 activation that invokes rotation of an S6 asparagine. Kasimova MA, Yazici AT, Yudin Y, Granata D, Klein ML, Rohacs T, Carnevale V. J Gen Physiol 150 1554-1566 (2018)
  4. Conserved allosteric pathways for activation of TRPV3 revealed through engineering vanilloid-sensitivity. Zhang F, Swartz KJ, Jara-Oseguera A. Elife 8 e42756 (2019)
  5. Interfacial Binding Sites for Cholesterol on TRP Ion Channels. Lee AG. Biophys J 117 2020-2033 (2019)
  6. Applications of Cryo-EM in small molecule and biologics drug design. Lees JA, Dias JM, Han S. Biochem Soc Trans 49 2627-2638 (2021)
  7. TRPV1 channels as a newly identified target for vitamin D. Long W, Johnson J, Kalyaanamoorthy S, Light P. Channels (Austin) 15 360-374 (2021)
  8. Non-canonical helical transitions and conformational switching are associated with characteristic flexibility and disorder indices in TRP and Kv channels. García-Morales A, Balleza D. Channels (Austin) 17 2212349 (2023)
  9. Modeling the structural and dynamical changes of the epithelial calcium channel TRPV5 caused by the A563T variation based on the structure of TRPV6. Wang L, Holmes RP, Peng JB. J Biomol Struct Dyn 37 3506-3512 (2019)


Reviews citing this publication (24)

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  14. Structural biology of thermoTRPV channels. Yuan P. Cell Calcium 84 102106 (2019)
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  16. High-resolution structures of transient receptor potential vanilloid channels: Unveiling a functionally diverse group of ion channels. van Goor MK, de Jager L, Cheng Y, van der Wijst J. Protein Sci 29 1569-1580 (2020)
  17. Druggable Lipid Binding Sites in Pentameric Ligand-Gated Ion Channels and Transient Receptor Potential Channels. Cheng WWL, Arcario MJ, Petroff JT. Front Physiol 12 798102 (2021)
  18. Modulation and Regulation of Canonical Transient Receptor Potential 3 (TRPC3) Channels. Cole BA, Becker EBE. Cells 12 2215 (2023)
  19. TRPM2: bridging calcium and ROS signaling pathways-implications for human diseases. Maliougina M, El Hiani Y. Front Physiol 14 1217828 (2023)
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  21. Alterations in the microenvironment and the effects produced of TRPV5 in osteoporosis. Luo ZH, Ma JX, Zhang W, Tian AX, Gong SW, Li Y, Lai YX, Ma XL. J Transl Med 21 327 (2023)
  22. Recent advances on the structure and the function relationships of the TRPV4 ion channel. Sánchez-Hernández R, Benítez-Angeles M, Hernández-Vega AM, Rosenbaum T. Channels (Austin) 18 2313323 (2024)
  23. Role of TRP Channels in Metabolism-Related Diseases. Wu F, Bu S, Wang H. Int J Mol Sci 25 692 (2024)
  24. Targeting TRP channels: recent advances in structure, ligand binding, and molecular mechanisms. Huang J, Korsunsky A, Yazdani M, Chen J. Front Mol Neurosci 16 1334370 (2023)

Articles citing this publication (37)

  1. Structure and gating mechanism of the transient receptor potential channel TRPV3. Singh AK, McGoldrick LL, Sobolevsky AI. Nat Struct Mol Biol 25 805-813 (2018)
  2. Molecular mechanism of TRPV2 channel modulation by cannabidiol. Pumroy RA, Samanta A, Liu Y, Hughes TE, Zhao S, Yudin Y, Rohacs T, Han S, Moiseenkova-Bell VY. Elife 8 e48792 (2019)
  3. Structure of the mouse TRPC4 ion channel. Duan J, Li J, Zeng B, Chen GL, Peng X, Zhang Y, Wang J, Clapham DE, Li Z, Zhang J. Nat Commun 9 3102 (2018)
  4. Structural bases of TRP channel TRPV6 allosteric modulation by 2-APB. Singh AK, Saotome K, McGoldrick LL, Sobolevsky AI. Nat Commun 9 2465 (2018)
  5. Electron cryo-microscopy structure of the canonical TRPC4 ion channel. Vinayagam D, Mager T, Apelbaum A, Bothe A, Merino F, Hofnagel O, Gatsogiannis C, Raunser S. Elife 7 e36615 (2018)
  6. Structural insight into TRPV5 channel function and modulation. Dang S, van Goor MK, Asarnow D, Wang Y, Julius D, Cheng Y, van der Wijst J. Proc Natl Acad Sci U S A 116 8869-8878 (2019)
  7. Structural basis for pharmacological modulation of the TRPC6 channel. Bai Y, Yu X, Chen H, Horne D, White R, Wu X, Lee P, Gu Y, Ghimire-Rijal S, Lin DC, Huang X. Elife 9 e53311 (2020)
  8. A Non-covalent Ligand Reveals Biased Agonism of the TRPA1 Ion Channel. Liu C, Reese R, Vu S, Rougé L, Shields SD, Kakiuchi-Kiyota S, Chen H, Johnson K, Shi YP, Chernov-Rogan T, Greiner DMZ, Kohli PB, Hackos D, Brillantes B, Tam C, Li T, Wang J, Safina B, Magnuson S, Volgraf M, Payandeh J, Zheng J, Rohou A, Chen J. Neuron 109 273-284.e4 (2021)
  9. Cryo-EM structure of the polycystin 2-l1 ion channel. Hulse RE, Li Z, Huang RK, Zhang J, Clapham DE. Elife 7 e36931 (2018)
  10. Structure-based characterization of novel TRPV5 inhibitors. Hughes TE, Del Rosario JS, Kapoor A, Yazici AT, Yudin Y, Fluck EC, Filizola M, Rohacs T, Moiseenkova-Bell VY. Elife 8 e49572 (2019)
  11. Extracellular cap domain is an essential component of the TRPV1 gating mechanism. Nadezhdin KD, Neuberger A, Nikolaev YA, Murphy LA, Gracheva EO, Bagriantsev SN, Sobolevsky AI. Nat Commun 12 2154 (2021)
  12. Global alignment and assessment of TRP channel transmembrane domain structures to explore functional mechanisms. Huffer KE, Aleksandrova AA, Jara-Oseguera A, Forrest LR, Swartz KJ. Elife 9 e58660 (2020)
  13. Lipid Interactions of a Ciliary Membrane TRP Channel: Simulation and Structural Studies of Polycystin-2. Wang Q, Corey RA, Hedger G, Aryal P, Grieben M, Nasrallah C, Baronina A, Pike ACW, Shi J, Carpenter EP, Sansom MSP. Structure 28 169-184.e5 (2020)
  14. Structural mechanism of TRPV3 channel inhibition by the plant-derived coumarin osthole. Neuberger A, Nadezhdin KD, Zakharian E, Sobolevsky AI. EMBO Rep 22 e53233 (2021)
  15. Structural mechanisms of TRPV6 inhibition by ruthenium red and econazole. Neuberger A, Nadezhdin KD, Sobolevsky AI. Nat Commun 12 6284 (2021)
  16. Structural Basis of TRPV4 N Terminus Interaction with Syndapin/PACSIN1-3 and PIP2. Goretzki B, Glogowski NA, Diehl E, Duchardt-Ferner E, Hacker C, Gaudet R, Hellmich UA. Structure 26 1583-1593.e5 (2018)
  17. Structural and Evolutionary Insights Point to Allosteric Regulation of TRP Ion Channels. Hilton JK, Kim M, Van Horn WD. Acc Chem Res 52 1643-1652 (2019)
  18. Structures of the TRPM5 channel elucidate mechanisms of activation and inhibition. Ruan Z, Haley E, Orozco IJ, Sabat M, Myers R, Roth R, Du J, Lü W. Nat Struct Mol Biol 28 604-613 (2021)
  19. Endocannabinoid activation of the TRPV1 ion channel is distinct from activation by capsaicin. Li Y, Chen X, Nie Y, Tian Y, Xiao X, Yang F. J Biol Chem 297 101022 (2021)
  20. Evidence that the TRPV1 S1-S4 membrane domain contributes to thermosensing. Kim M, Sisco NJ, Hilton JK, Montano CM, Castro MA, Cherry BR, Levitus M, Van Horn WD. Nat Commun 11 4169 (2020)
  21. Inactivation-mimicking block of the epithelial calcium channel TRPV6. Bhardwaj R, Lindinger S, Neuberger A, Nadezhdin KD, Singh AK, Cunha MR, Derler I, Gyimesi G, Reymond JL, Hediger MA, Romanin C, Sobolevsky AI. Sci Adv 6 eabe1508 (2020)
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  24. TRPA1 modulation by piperidine carboxamides suggests an evolutionarily conserved binding site and gating mechanism. Chernov-Rogan T, Gianti E, Liu C, Villemure E, Cridland AP, Hu X, Ballini E, Lange W, Deisemann H, Li T, Ward SI, Hackos DH, Magnuson S, Safina B, Klein ML, Volgraf M, Carnevale V, Chen J. Proc Natl Acad Sci U S A 116 26008-26019 (2019)
  25. Structure of the ancient TRPY1 channel from Saccharomyces cerevisiae reveals mechanisms of modulation by lipids and calcium. Ahmed T, Nisler CR, Fluck EC, Walujkar S, Sotomayor M, Moiseenkova-Bell VY. Structure 30 139-155.e5 (2022)
  26. Structural mechanism of human oncochannel TRPV6 inhibition by the natural phytoestrogen genistein. Neuberger A, Trofimov YA, Yelshanskaya MV, Nadezhdin KD, Krylov NA, Efremov RG, Sobolevsky AI. Nat Commun 14 2659 (2023)
  27. Structure of ABCB1/P-Glycoprotein in the Presence of the CFTR Potentiator Ivacaftor. Barbieri A, Thonghin N, Shafi T, Prince SM, Collins RF, Ford RC. Membranes (Basel) 11 923 (2021)
  28. Modulation of TRPV2 by endogenous and exogenous ligands: A computational study. Feng S, Pumroy RA, Protopopova AD, Moiseenkova-Bell VY, Im W. Protein Sci 32 e4490 (2023)
  29. Production and purification of TRPV2 and TRPV5 for structural and functional studies. Fluck EC, Pumroy RA, Moiseenkova-Bell VY. Methods Enzymol 653 49-74 (2021)
  30. Association of TRPV5, CASR, and CALCR genetic variants with kidney stone disease susceptibility in Egyptians through main effects and gene-gene interactions. Ali FT, El-Azeem EMA, Hekal HFA, El-Gizawy MM, Sayed MS, Mandoh AY, Soliman AF. Urolithiasis 50 701-710 (2022)
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  35. A Biocompatible Liquid Pillar[n]arene-Based Drug Reservoir for Topical Drug Delivery. Zhang Y, Ma M, Chen L, Du X, Meng Z, Zhang H, Zheng Z, Chen J, Meng Q. Pharmaceutics 14 2621 (2022)
  36. Structural mechanism of TRPV5 inhibition by econazole. De Jesús-Pérez JJ, Gabrielle M, Raheem S, Fluck EC, Rohacs T, Moiseenkova-Bell VY. Structure 32 148-156.e5 (2024)
  37. Yeast as a tool for membrane protein production and structure determination. Carlesso A, Delgado R, Ruiz Isant O, Uwangue O, Valli D, Bill RM, Hedfalk K. FEMS Yeast Res 22 foac047 (2022)


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