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Structural basis for human TRPC5 channel inhibition by two distinct inhibitors.

<div class='caption-title'>(A, B) Inhibitory effect of clemizole (CMZ) (A) and HC-070 (B) on the extracellular calcium-induced intracellular calcium increase of cells with wild-type hTRPC5 over-expression measured by FLIPR calcium assay (data are shown as means ± standard error, n = 3 independent experiments). (C, D) Cryo-EM density maps of CMZ-bound hTRPC5 shown in side view (C) and top view (D). Subunits A, B, C, and D are colored in purple, light blue, orange, and gray, respectively. Lipids are colored in gold. The approximate boundary of the cell membrane is indicated by gray lines. TMD, transmembrane domain; ICD, intracellular cytosolic domain. (E) Ribbon diagram of a single subunit with secondary structure elements represented in different colors. ARD, ankyrin repeats domain; LHD, linker-helix domain; CH1, C-terminal helix 1; CH2, C-terminal helix 2.</div>
<div class='caption-title'>Biochemical and functional characterization of human TRPC5 (hTRPC5) constructs.</div>
<div class='caption-title'>Cryo-EM image analysis of apo human TRPC5 (hTRPC5).</div>
Song K, Wei M, Guo W, Quan L, Kang Y, Wu JX, Chen L
OpenAccess logo Elife 10 (2021)
Related entries: 7d4p, 7e4t

Cited: 22 times
EuropePMC logo PMID: 33683200

Abstract

TRPC5 channel is a nonselective cation channel that participates in diverse physiological processes. TRPC5 inhibitors show promise in the treatment of anxiety disorder, depression, and kidney disease. However, the binding sites and inhibitory mechanism of TRPC5 inhibitors remain elusive. Here, we present the cryo-EM structures of human TRPC5 in complex with two distinct inhibitors, namely clemizole and HC-070, to the resolution of 2.7 Å. The structures reveal that clemizole binds inside the voltage sensor-like domain of each subunit. In contrast, HC-070 is wedged between adjacent subunits and replaces the glycerol group of a putative diacylglycerol molecule near the extracellular side. Moreover, we found mutations in the inhibitor binding pockets altered the potency of inhibitors. These structures suggest that both clemizole and HC-070 exert the inhibitory functions by stabilizing the ion channel in a nonconductive closed state. These results pave the way for further design and optimization of inhibitors targeting human TRPC5.

Reviews - 7d4q mentioned but not cited (1)

  1. Pose Classification Using Three-Dimensional Atomic Structure-Based Neural Networks Applied to Ion Channel-Ligand Docking. Shim H, Kim H, Allen JE, Wulff H. J Chem Inf Model 62 2301-2315 (2022)

Articles - 7d4q mentioned but not cited (1)

  1. Structural basis for human TRPC5 channel inhibition by two distinct inhibitors. Song K, Wei M, Guo W, Quan L, Kang Y, Wu JX, Chen L. Elife 10 e63429 (2021)


Reviews citing this publication (7)

  1. Ligand-Binding Sites in Vanilloid-Subtype TRP Channels. Yelshanskaya MV, Sobolevsky AI. Front Pharmacol 13 900623 (2022)
  2. TRPC channels as emerging targets for seizure disorders. Yu Y, Li W, Jiang J. Trends Pharmacol Sci 43 787-798 (2022)
  3. Modulation and Regulation of Canonical Transient Receptor Potential 3 (TRPC3) Channels. Cole BA, Becker EBE. Cells 12 2215 (2023)
  4. Simulation and Machine Learning Methods for Ion-Channel Structure Determination, Mechanistic Studies and Drug Design. Zhu Z, Deng Z, Wang Q, Wang Y, Zhang D, Xu R, Guo L, Wen H. Front Pharmacol 13 939555 (2022)
  5. TRP (transient receptor potential) ion channel family: structures, biological functions and therapeutic interventions for diseases. Zhang M, Ma Y, Ye X, Zhang N, Pan L, Wang B. Signal Transduct Target Ther 8 261 (2023)
  6. TRP channels: a journey towards a molecular understanding of pain. Rosenbaum T, Morales-Lázaro SL, Islas LD. Nat Rev Neurosci 23 596-610 (2022)
  7. The Role of Membrane Lipids in Light-Activation of Drosophila TRP Channels. Gutorov R, Katz B, Rhodes-Mordov E, Zaguri R, Brandwine-Shemmer T, Minke B. Biomolecules 12 382 (2022)

Articles citing this publication (13)

  1. Structural basis of TRPC4 regulation by calmodulin and pharmacological agents. Vinayagam D, Quentin D, Yu-Strzelczyk J, Sitsel O, Merino F, Stabrin M, Hofnagel O, Yu M, Ledeboer MW, Nagel G, Malojcic G, Raunser S. Elife 9 e60603 (2020)
  2. Transient receptor potential canonical 5 mediates inflammatory mechanical and spontaneous pain in mice. Sadler KE, Moehring F, Shiers SI, Laskowski LJ, Mikesell AR, Plautz ZR, Brezinski AN, Mecca CM, Dussor G, Price TJ, McCorvy JD, Stucky CL. Sci Transl Med 13 eabd7702 (2021)
  3. Diacylglycerols interact with the L2 lipidation site in TRPC3 to induce a sensitized channel state. Erkan-Candag H, Clarke A, Tiapko O, Gsell MA, Stockner T, Groschner K. EMBO Rep 23 e54276 (2022)
  4. 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)
  5. Sequence and structural conservation reveal fingerprint residues in TRP channels. Cabezas-Bratesco D, Mcgee FA, Colenso CK, Zavala K, Granata D, Carnevale V, Opazo JC, Brauchi SE. Elife 11 e73645 (2022)
  6. Hydrophobic interactions within the C terminus pole helices tunnel regulate calcium-dependent inactivation of TRPC3 in a calmodulin-dependent manner. Wijerathne T, Lin WY, Cooray A, Muallem S, Lee KP. Cell Calcium 109 102684 (2023)
  7. Interactions between the Polysialylated Neural Cell Adhesion Molecule and the Transient Receptor Potential Canonical Channels 1, 4, and 5 Induce Entry of Ca2+ into Neurons. Amores-Bonet L, Kleene R, Theis T, Schachner M. Int J Mol Sci 23 10027 (2022)
  8. Molecular architecture of the Gαi-bound TRPC5 ion channel. Won J, Kim J, Jeong H, Kim J, Feng S, Jeong B, Kwak M, Ko J, Im W, So I, Lee HH. Nat Commun 14 2550 (2023)
  9. Nonselective TRPC channel inhibition and suppression of aminoglycoside-induced premature termination codon readthrough by the small molecule AC1903. Baradaran-Heravi A, Bauer CC, Pickles IB, Hosseini-Farahabadi S, Balgi AD, Choi K, Linley DM, Beech DJ, Roberge M, Bon RS. J Biol Chem 298 101546 (2022)
  10. Radiosynthesis and Evaluation of a C-11 Radiotracer for Transient Receptor Potential Canonical 5 in the Brain. Yu Y, Jiang H, Liang Q, Qiu L, Huang T, Hu H, Bolshakov VY, Perlmutter JS, Tu Z. Mol Imaging Biol 25 334-342 (2023)
  11. Letter Structural identification of riluzole-binding site on human TRPC5. Yang Y, Wei M, Chen L. Cell Discov 8 67 (2022)
  12. TRPC3 channel gating by lipids requires localization at the ER/PM junctions defined by STIM1. Liu H, Lin WY, Leibow SR, Morateck AJ, Ahuja M, Muallem S. J Cell Biol 221 e202107120 (2022)
  13. [Overexpression of miR-607 inhibits hepatocellular carcinoma cell growth and metastasis by down-regulating TRPC5]. Li C, Chen S, Jiang Y. Nan Fang Yi Ke Da Xue Xue Bao 42 1587-1593 (2022)


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