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Binding of cardiotonic steroids to Na+,K+-ATPase in the E2P state.

Kanai R, Cornelius F, Ogawa H, Motoyama K, Vilsen B, Toyoshima C
Proc Natl Acad Sci U S A 118 (2021)
Related entries: 7d91, 7d92, 7d93, 7d94, 7ddf, 7ddh, 7ddi, 7ddl

Cited: 23 times
EuropePMC logo PMID: 33318128

Abstract

The sodium pump (Na+, K+-ATPase, NKA) is vital for animal cells, as it actively maintains Na+ and K+ electrochemical gradients across the cell membrane. It is a target of cardiotonic steroids (CTSs) such as ouabain and digoxin. As CTSs are almost unique strong inhibitors specific to NKA, a wide range of derivatives has been developed for potential therapeutic use. Several crystal structures have been published for NKA-CTS complexes, but they fail to explain the largely different inhibitory properties of the various CTSs. For instance, although CTSs are thought to inhibit ATPase activity by binding to NKA in the E2P state, we do not know if large conformational changes accompany binding, as no crystal structure is available for the E2P state free of CTS. Here, we describe crystal structures of the BeF3 - complex of NKA representing the E2P ground state and then eight crystal structures of seven CTSs, including rostafuroxin and istaroxime, two new members under clinical trials, in complex with NKA in the E2P state. The conformations of NKA are virtually identical in all complexes with and without CTSs, showing that CTSs bind to a preformed cavity in NKA. By comparing the inhibitory potency of the CTSs measured under four different conditions, we elucidate how different structural features of the CTSs result in different inhibitory properties. The crystal structures also explain K+-antagonism and suggest a route to isoform specific CTSs.

Reviews citing this publication (7)

  1. Diseases caused by mutations in the Na+/K+ pump α1 gene ATP1A1. Biondo ED, Spontarelli K, Ababioh G, Méndez L, Artigas P. Am J Physiol Cell Physiol 321 C394-C408 (2021)
  2. Protective Effects of Caesalpinia sappan Linn. and Its Bioactive Compounds on Cardiovascular Organs. Syamsunarno MRA, Safitri R, Kamisah Y. Front Pharmacol 12 725745 (2021)
  3. Efficacy of the New Inotropic Agent Istaroxime in Acute Heart Failure. Forzano I, Mone P, Mottola G, Kansakar U, Salemme L, De Luca A, Tesorio T, Varzideh F, Santulli G. J Clin Med 11 7503 (2022)
  4. Na+,K+-ATPase and Cardiotonic Steroids in Models of Dopaminergic System Pathologies. Markina AA, Kazanskaya RB, Timoshina JA, Zavialov VA, Abaimov DA, Volnova AB, Fedorova TN, Gainetdinov RR, Lopachev AV. Biomedicines 11 1820 (2023)
  5. Start Me Up: How Can Surrounding Gangliosides Affect Sodium-Potassium ATPase Activity and Steer towards Pathological Ion Imbalance in Neurons? Puljko B, Stojanović M, Ilic K, Kalanj-Bognar S, Mlinac-Jerkovic K. Biomedicines 10 1518 (2022)
  6. The Na+,K+-ATPase and its stoichiometric ratio: some thermodynamic speculations. Peluffo RD, Hernández JA. Biophys Rev 15 539-552 (2023)
  7. The vascular Na,K-ATPase: clinical implications in stroke, migraine, and hypertension. Staehr C, Aalkjaer C, Matchkov VV. Clin Sci (Lond) 137 1595-1618 (2023)

Articles citing this publication (16)

  1. Structural and energetic analysis of metastable intermediate states in the E1P-E2P transition of Ca2+-ATPase. Kobayashi C, Matsunaga Y, Jung J, Sugita Y. Proc Natl Acad Sci U S A 118 e2105507118 (2021)
  2. Cryo-EM structures of recombinant human sodium-potassium pump determined in three different states. Guo Y, Zhang Y, Yan R, Huang B, Ye F, Wu L, Chi X, Shi Y, Zhou Q. Nat Commun 13 3957 (2022)
  3. Na,K-ATPase α4, and Not Na,K-ATPase α1, is the Main Contributor to Sperm Motility, But its High Ouabain Binding Affinity Site is Not Required for Male Fertility in Mice. McDermott JP, Sánchez G, Mitra A, Numata S, Liu LC, Blanco G. J Membr Biol 254 549-561 (2021)
  4. The Na+/K+ pump dominates control of glycolysis in hippocampal dentate granule cells. Meyer DJ, Díaz-García CM, Nathwani N, Rahman M, Yellen G. Elife 11 e81645 (2022)
  5. Cryoelectron microscopy of Na+,K+-ATPase in the two E2P states with and without cardiotonic steroids. Kanai R, Cornelius F, Vilsen B, Toyoshima C. Proc Natl Acad Sci U S A 119 e2123226119 (2022)
  6. Depth of the Steroid Core Location Determines the Mode of Na,K-ATPase Inhibition by Cardiotonic Steroids. Tverskoi AM, Poluektov YM, Klimanova EA, Mitkevich VA, Makarov AA, Orlov SN, Petrushanko IY, Lopina OD. Int J Mol Sci 22 13268 (2021)
  7. Gastric proton pump with two occluded K+ engineered with sodium pump-mimetic mutations. Abe K, Yamamoto K, Irie K, Nishizawa T, Oshima A. Nat Commun 12 5709 (2021)
  8. Structural basis for gating mechanism of the human sodium-potassium pump. Nguyen PT, Deisl C, Fine M, Tippetts TS, Uchikawa E, Bai XC, Levine B. Nat Commun 13 5293 (2022)
  9. Cytotoxic effect of carbohydrate derivatives of digitoxigenin involves modulation of plasma membrane Ca2+ -ATPase. Valadares JMM, Bajaj SO, Li H, Wang HL, Silva SC, Garcia IJP, Pereira DG, Azalim P, Quintas LEM, Noël F, Cortes VF, O'Doherty GA, Barbosa LA. J Cell Biochem 122 1903-1914 (2021)
  10. Epistatic Effects Between Amino Acid Insertions and Substitutions Mediate Toxin resistance of Vertebrate Na+,K+-ATPases. Mohammadi S, Özdemir Hİ, Ozbek P, Sumbul F, Stiller J, Deng Y, Crawford AJ, Rowland HM, Storz JF, Andolfatto P, Dobler S. Mol Biol Evol 39 msac258 (2022)
  11. Fluorescence lifetime imaging microscopy reveals sodium pump dimers in live cells. Seflova J, Habibi NR, Yap JQ, Cleary SR, Fang X, Kekenes-Huskey PM, Espinoza-Fonseca LM, Bossuyt JB, Robia SL. J Biol Chem 298 101865 (2022)
  12. Na + /K + -ATPase regulates the K + /Na + homeostasis in the intertidal macroalgae, Neoporphyra haitanensis, in response to salt stress. Chen Q, Xu K, Xu Y, Ji D, Chen C, Xie C, Wang W. Front Plant Sci 13 1040142 (2022)
  13. Exploring the Phospholipid Transport Mechanism of ATP8A1-CDC50. Zhang H, Zhang Y, Xu P, Bai C. Biomedicines 11 546 (2023)
  14. Identification of the NA+/K+-ATPase α-Isoforms in Six Species of Poison Dart Frogs and their Sensitivity to Cardiotonic Steroids. Medina-Ortiz K, Navia F, Mosquera-Gil C, Sánchez A, Sterling G, Fierro L, Castaño S. J Chem Ecol 49 116-132 (2023)
  15. Temperature instability of a mutation at a multidomain junction in Na,K-ATPase isoform ATP1A3 (p.Arg756His) produces a fever-induced neurological syndrome. Arystarkhova E, Toustrup-Jensen MS, Holm R, Ko JK, Lee KE, Feschenko P, Ozelius LJ, Brashear A, Vilsen B, Sweadner KJ. J Biol Chem 299 102758 (2023)
  16. The Na+,K+-ATPase in complex with beryllium fluoride mimics an ATPase phosphorylated state. Fruergaard MU, Dach I, Andersen JL, Ozol M, Shahsavar A, Quistgaard EM, Poulsen H, Fedosova NU, Nissen P. J Biol Chem 298 102317 (2022)


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