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Structural Basis for Pore Blockade of the Human Cardiac Sodium Channel Nav 1.5 by the Antiarrhythmic Drug Quinidine*.

Li Z, Jin X, Wu T, Huang G, Wu K, Lei J, Pan X, Yan N
Angew Chem Int Ed Engl 60 11474-11480 (2021)
Cited: 45 times
EuropePMC logo PMID: 33684260

Abstract

Nav 1.5, the primary voltage-gated Na+ (Nav ) channel in heart, is a major target for class I antiarrhythmic agents. Here we present the cryo-EM structure of full-length human Nav 1.5 bound to quinidine, a class Ia antiarrhythmic drug, at 3.3 Å resolution. Quinidine is positioned right beneath the selectivity filter in the pore domain and coordinated by residues from repeats I, III, and IV. Pore blockade by quinidine is achieved through both direct obstruction of the ion permeation path and induced rotation of an invariant Tyr residue that tightens the intracellular gate. Structural comparison with a truncated rat Nav 1.5 in the presence of flecainide, a class Ic agent, reveals distinct binding poses for the two antiarrhythmics within the pore domain. Our work reported here, along with previous studies, reveals the molecular basis for the mechanism of action of class I antiarrhythmic drugs.

Reviews - 6lqa mentioned but not cited (6)

  1. A structural atlas of druggable sites on Nav channels. Li Z, Wu Q, Yan N. Channels (Austin) 18 2287832 (2024)
  2. P-Loop Channels: Experimental Structures, and Physics-Based and Neural Networks-Based Models. Tikhonov DB, Zhorov BS. Membranes (Basel) 12 229 (2022)
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  4. Sodium Channels and Local Anesthetics-Old Friends With New Perspectives. Körner J, Albani S, Sudha Bhagavath Eswaran V, Roehl AB, Rossetti G, Lampert A. Front Pharmacol 13 837088 (2022)
  5. Structural Advances in Voltage-Gated Sodium Channels. Jiang D, Zhang J, Xia Z. Front Pharmacol 13 908867 (2022)
  6. When the Gates Swing Open Only: Arrhythmia Mutations That Target the Fast Inactivation Gate of Nav1.5. Gamal El-Din TM. Cells 11 3714 (2022)

Articles - 6lqa mentioned but not cited (13)

  1. Structure of human Nav1.5 reveals the fast inactivation-related segments as a mutational hotspot for the long QT syndrome. Li Z, Jin X, Wu T, Zhao X, Wang W, Lei J, Pan X, Yan N. Proc Natl Acad Sci U S A 118 e2100069118 (2021)
  2. Possible Interactions of Extracellular Loop IVP2-S6 With Voltage-Sensing Domain III in Cardiac Sodium Channel. Zaytseva AK, Boitsov AS, Kostareva AA, Zhorov BS. Front Pharmacol 12 742508 (2021)
  3. Structural basis for high-voltage activation and subtype-specific inhibition of human Nav1.8. Huang X, Jin X, Huang G, Huang J, Wu T, Li Z, Chen J, Kong F, Pan X, Yan N. Proc Natl Acad Sci U S A 119 e2208211119 (2022)
  4. Functional cross-talk between phosphorylation and disease-causing mutations in the cardiac sodium channel Nav1.5. Galleano I, Harms H, Choudhury K, Khoo K, Delemotte L, Pless SA. Proc Natl Acad Sci U S A 118 e2025320118 (2021)
  5. Intersegment Contacts of Potentially Damaging Variants of Cardiac Sodium Channel. Korkosh VS, Zaytseva AK, Kostareva AA, Zhorov BS. Front Pharmacol 12 756415 (2021)
  6. Genetic Profile and Clinical Characteristics of Brugada Syndrome in the Chinese Population. Wang LL, Chen YH, Sun Y, Huang M, Wei HR, Liu H, Xu K, Song XL, Chen P, Tan L, Huang J, Li ZZ, Li R, Yu T, Ma F, Ding H, Wang Y, Wang DW, Wang H, Zhao CX. J Cardiovasc Dev Dis 9 369 (2022)
  7. Inhibitory Effects of Nobiletin on Voltage-Gated Na+ Channel in Rat Ventricular Myocytes Based on Electrophysiological Analysis and Molecular Docking Method. Gu Y, Wang J, Li M, Zhong F, Xiang J, Xu Z. Int J Mol Sci 23 15175 (2022)
  8. Insights into the Cardiotoxic Effects of Veratrum Lobelianum Alkaloids: Pilot Study. Taldaev A, Terekhov RP, Melnik EV, Belova MV, Kozin SV, Nedorubov AA, Pomerantseva TY, Ramenskaya GV. Toxins (Basel) 14 490 (2022)
  9. Molecular Modeling of Cardiac Sodium Channel with Mexiletine. Zhorov BS. Membranes (Basel) 12 1252 (2022)
  10. Spliced isoforms of the cardiac Nav1.5 channel modify channel activation by distinct structural mechanisms. Mancino AS, Glass WG, Yan Y, Biggin PC, Bowie D. J Gen Physiol 154 e202112906 (2022)
  11. Synthesis and In Vivo Antiarrhythmic Activity Evaluation of Novel Scutellarein Analogues as Voltage-Gated Nav1.5 and Cav1.2 Channels Blockers. Yang W, Wang W, Cai S, Li P, Zhang D, Ning J, Ke J, Hou A, Chen L, Ma Y, Jin W. Molecules 28 7417 (2023)
  12. Synthesis, Pharmacological Evaluation, and Molecular Modeling of Lappaconitine-1,5-Benzodiazepine Hybrids. Cheremnykh KP, Bryzgalov AO, Baev DS, Borisov SA, Sotnikova YS, Savelyev VA, Tolstikova TG, Sagdullaev SS, Shults EE. Molecules 28 4234 (2023)
  13. Veratridine Can Bind to a Site at the Mouth of the Channel Pore at Human Cardiac Sodium Channel NaV1.5. Gulsevin A, Glazer AM, Shields T, Kroncke BM, Roden DM, Meiler J. Int J Mol Sci 23 2225 (2022)


Reviews citing this publication (5)

  1. Voltage gated sodium and calcium channels: Discovery, structure, function, and Pharmacology. Catterall WA. Channels (Austin) 17 2281714 (2023)
  2. Chemical and Biological Tools for the Study of Voltage-Gated Sodium Channels in Electrogenesis and Nociception. Elleman AV, Du Bois J. Chembiochem 23 e202100625 (2022)
  3. Druggability of Voltage-Gated Sodium Channels-Exploring Old and New Drug Receptor Sites. Wisedchaisri G, Gamal El-Din TM. Front Pharmacol 13 858348 (2022)
  4. Fenestropathy of Voltage-Gated Sodium Channels. Gamal El-Din TM, Lenaeus MJ. Front Pharmacol 13 842645 (2022)
  5. Genetics of congenital arrhythmia syndromes: the challenge of variant interpretation. Glazer AM. Curr Opin Genet Dev 77 102004 (2022)

Articles citing this publication (21)

  1. Structure of human Cav2.2 channel blocked by the painkiller ziconotide. Gao S, Yao X, Yan N. Nature 596 143-147 (2021)
  2. Unwinding and spiral sliding of S4 and domain rotation of VSD during the electromechanical coupling in Nav1.7. Huang G, Wu Q, Li Z, Jin X, Huang X, Wu T, Pan X, Yan N. Proc Natl Acad Sci U S A 119 e2209164119 (2022)
  3. Differences in local anaesthetic and antiepileptic binding in the inactivated state of human sodium channel Nav1.4. Buyan A, Whitfield AA, Corry B. Biophys J 120 5553-5563 (2021)
  4. Characterizing fenestration size in sodium channel subtypes and their accessibility to inhibitors. Tao E, Corry B. Biophys J 121 193-206 (2022)
  5. Molecular Pathology of Sodium Channel Beta-Subunit Variants. Angsutararux P, Zhu W, Voelker TL, Silva JR. Front Pharmacol 12 761275 (2021)
  6. Structural mapping of Nav1.7 antagonists. Wu Q, Huang J, Fan X, Wang K, Jin X, Huang G, Li J, Pan X, Yan N. Nat Commun 14 3224 (2023)
  7. A mechanistic reinterpretation of fast inactivation in voltage-gated Na+ channels. Liu Y, Bassetto CAZ, Pinto BI, Bezanilla F. Nat Commun 14 5072 (2023)
  8. An open state of a voltage-gated sodium channel involving a π-helix and conserved pore-facing asparagine. Choudhury K, Kasimova MA, McComas S, Howard RJ, Delemotte L. Biophys J 121 11-22 (2022)
  9. An α-π transition in S6 shapes the conformational cycle of the bacterial sodium channel NavAb. Choudhury K, Howard RJ, Delemotte L. J Gen Physiol 155 e202213214 (2023)
  10. Cannabidiol inhibits Nav channels through two distinct binding sites. Huang J, Fan X, Jin X, Jo S, Zhang HB, Fujita A, Bean BP, Yan N. Nat Commun 14 3613 (2023)
  11. Clinical characteristics and electrophysiologic properties of SCN5A variants in fever-induced Brugada syndrome. Chen GX, Barajas-Martínez H, Ciconte G, Wu CI, Monasky MM, Xia H, Li B, Capra JA, Guo K, Zhang ZH, Chen X, Yang B, Jiang H, Tse G, Mak CM, Aizawa Y, Gollob MH, Antzelevitch C, Wilde AAM, Pappone C, Hu D. EBioMedicine 87 104388 (2022)
  12. Computational methods and theory for ion channel research. Guardiani C, Cecconi F, Chiodo L, Cottone G, Malgaretti P, Maragliano L, Barabash ML, Camisasca G, Ceccarelli M, Corry B, Roth R, Giacomello A, Roux B. Adv Phys X 7 2080587 (2022)
  13. Dual-pocket inhibition of Nav channels by the antiepileptic drug lamotrigine. Huang J, Fan X, Jin X, Teng L, Yan N. Proc Natl Acad Sci U S A 120 e2309773120 (2023)
  14. Extracellular hemin is a reverse use-dependent gating modifier of cardiac voltage-gated Na+ channels. Gessner G, Jamili M, Tomczyk P, Menche D, Schönherr R, Hoshi T, Heinemann SH. Biol Chem 403 1067-1081 (2022)
  15. Modulation of Pore Opening of Eukaryotic Sodium Channels by π-Helices in S6. Choudhury K, Delemotte L. J Phys Chem Lett 14 5876-5881 (2023)
  16. Protein 14-3-3 Influences the Response of the Cardiac Sodium Channel Nav1.5 to Antiarrhythmic Drugs. Zheng Y, Deschênes I. J Pharmacol Exp Ther 384 417-428 (2023)
  17. Structural basis for NaV1.7 inhibition by pore blockers. Zhang J, Shi Y, Huang Z, Li Y, Yang B, Gong J, Jiang D. Nat Struct Mol Biol 29 1208-1216 (2022)
  18. Structural basis for modulation of human NaV1.3 by clinical drug and selective antagonist. Li X, Xu F, Xu H, Zhang S, Gao Y, Zhang H, Dong Y, Zheng Y, Yang B, Sun J, Zhang XC, Zhao Y, Jiang D. Nat Commun 13 1286 (2022)
  19. Structure-guided unlocking of NaX reveals a non-selective tetrodotoxin-sensitive cation channel. Noland CL, Chua HC, Kschonsak M, Heusser SA, Braun N, Chang T, Tam C, Tang J, Arthur CP, Ciferri C, Pless SA, Payandeh J. Nat Commun 13 1416 (2022)
  20. Unravelling Novel SCN5A Mutations Linked to Brugada Syndrome: Functional, Structural, and Genetic Insights. Frosio A, Micaglio E, Polsinelli I, Calamaio S, Melgari D, Prevostini R, Ghiroldi A, Binda A, Carrera P, Villa M, Mastrocinque F, Presi S, Salerno R, Boccellino A, Anastasia L, Ciconte G, Ricagno S, Pappone C, Rivolta I. Int J Mol Sci 24 15089 (2023)
  21. VGSC-DB: an online database of voltage-gated sodium channels. Wang G, Yu J, Du H, Shen C, Zhang X, Liu Y, Zhang Y, Cao D, Pan P, Hou T. J Cheminform 14 75 (2022)


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