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Cryo-EM structures of apo and antagonist-bound human Cav3.1.

Zhao Y, Huang G, Wu Q, Wu K, Li R, Lei J, Pan X, Yan N
Nature 576 492-497 (2019)
Cited: 72 times
EuropePMC logo PMID: 31766050

Abstract

Among the ten subtypes of mammalian voltage-gated calcium (Cav) channels, Cav3.1-Cav3.3 constitute the T-type, or the low-voltage-activated, subfamily, the abnormal activities of which are associated with epilepsy, psychiatric disorders and pain1-5. Here we report the cryo-electron microscopy structures of human Cav3.1 alone and in complex with a highly Cav3-selective blocker, Z9446,7, at resolutions of 3.3 Å and 3.1 Å, respectively. The arch-shaped Z944 molecule reclines in the central cavity of the pore domain, with the wide end inserting into the fenestration on the interface between repeats II and III, and the narrow end hanging above the intracellular gate like a plug. The structures provide the framework for comparative investigation of the distinct channel properties of different Cav subfamilies.

Reviews - 6kzo mentioned but not cited (2)

  1. P-Loop Channels: Experimental Structures, and Physics-Based and Neural Networks-Based Models. Tikhonov DB, Zhorov BS. Membranes (Basel) 12 229 (2022)
  2. Structural biology of voltage-gated calcium channels. Yao X, Gao S, Yan N. Channels (Austin) 18 2290807 (2024)

Articles - 6kzo mentioned but not cited (12)



Reviews citing this publication (19)

  1. Presynaptic calcium channels: specialized control of synaptic neurotransmitter release. Dolphin AC, Lee A. Nat Rev Neurosci 21 213-229 (2020)
  2. De novo CACNA1D Ca2+ channelopathies: clinical phenotypes and molecular mechanism. Ortner NJ, Kaserer T, Copeland JN, Striessnig J. Pflugers Arch 472 755-773 (2020)
  3. Neuronal Cav3 channelopathies: recent progress and perspectives. Lory P, Nicole S, Monteil A. Pflugers Arch 472 831-844 (2020)
  4. Cryo-EM as a powerful tool for drug discovery. Van Drie JH, Tong L. Bioorg Med Chem Lett 30 127524 (2020)
  5. Voltage-Gated Ca2+-Channel α1-Subunit de novo Missense Mutations: Gain or Loss of Function - Implications for Potential Therapies. Striessnig J. Front Synaptic Neurosci 13 634760 (2021)
  6. Central and peripheral contributions of T-type calcium channels in pain. Harding EK, Zamponi GW. Mol Brain 15 39 (2022)
  7. Druggability of Voltage-Gated Sodium Channels-Exploring Old and New Drug Receptor Sites. Wisedchaisri G, Gamal El-Din TM. Front Pharmacol 13 858348 (2022)
  8. Opioid Receptor Regulation of Neuronal Voltage-Gated Calcium Channels. Weiss N, Zamponi GW. Cell Mol Neurobiol 41 839-847 (2021)
  9. Designer genetically encoded voltage-dependent calcium channel inhibitors inspired by RGK GTPases. Colecraft HM. J Physiol 598 1683-1693 (2020)
  10. Voltage gated sodium and calcium channels: Discovery, structure, function, and Pharmacology. Catterall WA. Channels (Austin) 17 2281714 (2023)
  11. Fenestropathy of Voltage-Gated Sodium Channels. Gamal El-Din TM, Lenaeus MJ. Front Pharmacol 13 842645 (2022)
  12. Ventricular voltage-gated ion channels: Detection, characteristics, mechanisms, and drug safety evaluation. Chen L, He Y, Wang X, Ge J, Li H. Clin Transl Med 11 e530 (2021)
  13. T-type calcium channels as therapeutic targets in essential tremor and Parkinson's disease. Matthews LG, Puryear CB, Correia SS, Srinivasan S, Belfort GM, Pan MK, Kuo SH. Ann Clin Transl Neurol 10 462-483 (2023)
  14. Pathology of pain and its implications for therapeutic interventions. Cao B, Xu Q, Shi Y, Zhao R, Li H, Zheng J, Liu F, Wan Y, Wei B. Signal Transduct Target Ther 9 155 (2024)
  15. Regulation of N-type calcium channels by nociceptin receptors and its possible role in neurological disorders. Caminski ES, Antunes FTT, Souza IA, Dallegrave E, Zamponi GW. Mol Brain 15 95 (2022)
  16. The T-type calcium channelosome. Weiss N, Zamponi GW. Pflugers Arch 476 163-177 (2024)
  17. Multi-target Phenylpropanoids Against Epilepsy. Rodrigues TCML, Dias AL, Dos Santos AMF, Monteiro AFM, Oliveira MCN, Pires HFO, de Sousa NF, da Silva Stiebbe Salvadori MG, Scotti MT, Scotti L. Curr Neuropharmacol 22 2168-2190 (2024)
  18. Peptide and Peptidomimetic Inhibitors Targeting the Interaction of Collapsin Response Mediator Protein 2 with the N-Type Calcium Channel for Pain Relief. Perez-Miller S, Gomez K, Khanna R. ACS Pharmacol Transl Sci 7 1916-1936 (2024)
  19. Structural biology and molecular pharmacology of voltage-gated ion channels. Huang J, Pan X, Yan N. Nat Rev Mol Cell Biol (2024)

Articles citing this publication (39)



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