4dw1 › Citations

Molecular mechanism of ATP binding and ion channel activation in P2X receptors.

Hattori M, Gouaux E
Nature 485 207-12 (2012)
Cited: 333 times
EuropePMC logo PMID: 22535247

Abstract

P2X receptors are trimeric ATP-activated ion channels permeable to Na+, K+ and Ca2+. The seven P2X receptor subtypes are implicated in physiological processes that include modulation of synaptic transmission, contraction of smooth muscle, secretion of chemical transmitters and regulation of immune responses. Despite the importance of P2X receptors in cellular physiology, the three-dimensional composition of the ATP-binding site, the structural mechanism of ATP-dependent ion channel gating and the architecture of the open ion channel pore are unknown. Here we report the crystal structure of the zebrafish P2X4 receptor in complex with ATP and a new structure of the apo receptor. The agonist-bound structure reveals a previously unseen ATP-binding motif and an open ion channel pore. ATP binding induces cleft closure of the nucleotide-binding pocket, flexing of the lower body β-sheet and a radial expansion of the extracellular vestibule. The structural widening of the extracellular vestibule is directly coupled to the opening of the ion channel pore by way of an iris-like expansion of the transmembrane helices. The structural delineation of the ATP-binding site and the ion channel pore, together with the conformational changes associated with ion channel gating, will stimulate development of new pharmacological agents.

Reviews - 4dw1 mentioned but not cited (12)

  1. P2X receptors as drug targets. North RA, Jarvis MF. Mol Pharmacol 83 759-769 (2013)
  2. Influences of membrane mimetic environments on membrane protein structures. Zhou HX, Cross TA. Annu Rev Biophys 42 361-392 (2013)
  3. Update of P2X receptor properties and their pharmacology: IUPHAR Review 30. Illes P, Müller CE, Jacobson KA, Grutter T, Nicke A, Fountain SJ, Kennedy C, Schmalzing G, Jarvis MF, Stojilkovic SS, King BF, Di Virgilio F. Br J Pharmacol 178 489-514 (2021)
  4. Principles and properties of ion flow in P2X receptors. Samways DS, Li Z, Egan TM. Front Cell Neurosci 8 6 (2014)
  5. The recombinant expression systems for structure determination of eukaryotic membrane proteins. He Y, Wang K, Yan N. Protein Cell 5 658-672 (2014)
  6. P2X4 receptors (P2X4Rs) represent a novel target for the development of drugs to prevent and/or treat alcohol use disorders. Franklin KM, Asatryan L, Jakowec MW, Trudell JR, Bell RL, Davies DL. Front Neurosci 8 176 (2014)
  7. Insights into the channel gating of P2X receptors from structures, dynamics and small molecules. Wang J, Yu Y. Acta Pharmacol Sin 37 44-55 (2016)
  8. Structural and Functional Features of the P2X4 Receptor: An Immunological Perspective. Kanellopoulos JM, Almeida-da-Silva CLC, Rüütel Boudinot S, Ojcius DM. Front Immunol 12 645834 (2021)
  9. Key sites for P2X receptor function and multimerization: overview of mutagenesis studies on a structural basis. Hausmann R, Kless A, Schmalzing G. Curr Med Chem 22 799-818 (2015)
  10. The P2X4 Receptor: Cellular and Molecular Characteristics of a Promising Neuroinflammatory Target. Sophocleous RA, Ooi L, Sluyter R. Int J Mol Sci 23 5739 (2022)
  11. Structural and molecular modeling features of P2X receptors. Alves LA, da Silva JH, Ferreira DN, Fidalgo-Neto AA, Teixeira PC, de Souza CA, Caffarena ER, de Freitas MS. Int J Mol Sci 15 4531-4549 (2014)
  12. Molecular Pharmacology of P2X Receptors: Exploring Druggable Domains Revealed by Structural Biology. Oken AC, Krishnamurthy I, Savage JC, Lisi NE, Godsey MH, Mansoor SE. Front Pharmacol 13 925880 (2022)

Articles - 4dw1 mentioned but not cited (69)



Reviews citing this publication (96)

  1. The P2X7 Receptor in Infection and Inflammation. Di Virgilio F, Dal Ben D, Sarti AC, Giuliani AL, Falzoni S. Immunity 47 15-31 (2017)
  2. Neuromodulation by extracellular ATP and P2X receptors in the CNS. Khakh BS, North RA. Neuron 76 51-69 (2012)
  3. The P2X7 Receptor in Inflammatory Diseases: Angel or Demon? Savio LEB, de Andrade Mello P, da Silva CG, Coutinho-Silva R. Front Pharmacol 9 52 (2018)
  4. Emerging Diversity in Lipid-Protein Interactions. Corradi V, Sejdiu BI, Mesa-Galloso H, Abdizadeh H, Noskov SY, Marrink SJ, Tieleman DP. Chem Rev 119 5775-5848 (2019)
  5. Allosteric Modulation as a Unifying Mechanism for Receptor Function and Regulation. Changeux JP, Christopoulos A. Cell 166 1084-1102 (2016)
  6. Medicinal chemistry of adenosine, P2Y and P2X receptors. Jacobson KA, Müller CE. Neuropharmacology 104 31-49 (2016)
  7. P2X receptor channels in chronic pain pathways. Bernier LP, Ase AR, Séguéla P. Br J Pharmacol 175 2219-2230 (2018)
  8. The P2X7 Receptor-Interleukin-1 Liaison. Giuliani AL, Sarti AC, Falzoni S, Di Virgilio F. Front Pharmacol 8 123 (2017)
  9. Neuronal P2X7 Receptors Revisited: Do They Really Exist? Illes P, Khan TM, Rubini P. J Neurosci 37 7049-7062 (2017)
  10. P2X receptors. North RA. Philos Trans R Soc Lond B Biol Sci 371 20150427 (2016)
  11. P2X7 in Cancer: From Molecular Mechanisms to Therapeutics. Lara R, Adinolfi E, Harwood CA, Philpott M, Barden JA, Di Virgilio F, McNulty S. Front Pharmacol 11 793 (2020)
  12. P2X4: A fast and sensitive purinergic receptor. Suurväli J, Boudinot P, Kanellopoulos J, Rüütel Boudinot S. Biomed J 40 245-256 (2017)
  13. Advances in recombinant protein expression for use in pharmaceutical research. Assenberg R, Wan PT, Geisse S, Mayr LM. Curr Opin Struct Biol 23 393-402 (2013)
  14. P2X4 Receptor Function in the Nervous System and Current Breakthroughs in Pharmacology. Stokes L, Layhadi JA, Bibic L, Dhuna K, Fountain SJ. Front Pharmacol 8 291 (2017)
  15. Purinergic signalling and diabetes. Burnstock G, Novak I. Purinergic Signal 9 307-324 (2013)
  16. Molecular structure and function of P2X receptors. Habermacher C, Dunning K, Chataigneau T, Grutter T. Neuropharmacology 104 18-30 (2016)
  17. Heteromeric assembly of P2X subunits. Saul A, Hausmann R, Kless A, Nicke A. Front Cell Neurosci 7 250 (2013)
  18. Multifaceted Effects of Extracellular Adenosine Triphosphate and Adenosine in the Tumor-Host Interaction and Therapeutic Perspectives. de Andrade Mello P, Coutinho-Silva R, Savio LEB. Front Immunol 8 1526 (2017)
  19. Ivermectin and its target molecules: shared and unique modulation mechanisms of ion channels and receptors by ivermectin. Chen IS, Kubo Y. J Physiol 596 1833-1845 (2018)
  20. P2X7 receptor antagonists: a patent review (2010-2015). Park JH, Kim YC. Expert Opin Ther Pat 27 257-267 (2017)
  21. Insight into DEG/ENaC channel gating from genetics and structure. Eastwood AL, Goodman MB. Physiology (Bethesda) 27 282-290 (2012)
  22. Seeking structural specificity: direct modulation of pentameric ligand-gated ion channels by alcohols and general anesthetics. Howard RJ, Trudell JR, Harris RA. Pharmacol Rev 66 396-412 (2014)
  23. The P2X7 receptor: shifting from a low- to a high-conductance channel - an enigmatic phenomenon? Alves LA, de Melo Reis RA, de Souza CA, de Freitas MS, Teixeira PC, Neto Moreira Ferreira D, Xavier RF. Biochim Biophys Acta 1838 2578-2587 (2014)
  24. P2RX7 Purinoceptor as a Therapeutic Target-The Second Coming? Young CNJ, Górecki DC. Front Chem 6 248 (2018)
  25. Exploring the ATP-binding site of P2X receptors. Chataigneau T, Lemoine D, Grutter T. Front Cell Neurosci 7 273 (2013)
  26. Short- and long-term (trophic) purinergic signalling. Burnstock G. Philos Trans R Soc Lond B Biol Sci 371 20150422 (2016)
  27. The Role of P2X7 Receptor in Alzheimer's Disease. Francistiová L, Bianchi C, Di Lauro C, Sebastián-Serrano Á, de Diego-García L, Kobolák J, Dinnyés A, Díaz-Hernández M. Front Mol Neurosci 13 94 (2020)
  28. Functional architecture of the CFTR chloride channel. Linsdell P. Mol Membr Biol 31 1-16 (2014)
  29. Inherent P2X7 Receptors Regulate Macrophage Functions during Inflammatory Diseases. Ren W, Rubini P, Tang Y, Engel T, Illes P. Int J Mol Sci 23 232 (2021)
  30. Pyroptosis and Its Role in Autoimmune Disease: A Potential Therapeutic Target. You R, He X, Zeng Z, Zhan Y, Xiao Y, Xiao R. Front Immunol 13 841732 (2022)
  31. ATP-induced Ca2+-signalling mechanisms in the regulation of mesenchymal stem cell migration. Jiang LH, Mousawi F, Yang X, Roger S. Cell Mol Life Sci 74 3697-3710 (2017)
  32. Non-synonymous single nucleotide polymorphisms in the P2X receptor genes: association with diseases, impact on receptor functions and potential use as diagnosis biomarkers. Caseley EA, Muench SP, Roger S, Mao HJ, Baldwin SA, Jiang LH. Int J Mol Sci 15 13344-13371 (2014)
  33. ATP as a cotransmitter in the autonomic nervous system. Kennedy C. Auton Neurosci 191 2-15 (2015)
  34. Motifs in the permeation pathway of connexin channels mediate voltage and Ca (2+) sensing. Harris AL, Contreras JE. Front Physiol 5 113 (2014)
  35. The Role of Connexin and Pannexin Channels in Perinatal Brain Injury and Inflammation. Zhou KQ, Green CR, Bennet L, Gunn AJ, Davidson JO. Front Physiol 10 141 (2019)
  36. Cryo-electron microscopy structures and progress toward a dynamic understanding of KATP channels. Puljung MC. J Gen Physiol 150 653-669 (2018)
  37. Allosteric modulation as a unifying mechanism for receptor function and regulation. Changeux JP, Christopoulos A. Diabetes Obes Metab 19 Suppl 1 4-21 (2017)
  38. Two open states of P2X receptor channels. Rokic MB, Stojilkovic SS. Front Cell Neurosci 7 215 (2013)
  39. Unanticipated parallels in architecture and mechanism between ATP-gated P2X receptors and acid sensing ion channels. Baconguis I, Hattori M, Gouaux E. Curr Opin Struct Biol 23 277-284 (2013)
  40. P2X4 receptors expressed on microglial cells in post-ischemic inflammation of brain ischemic injury. Cheng RD, Ren JJ, Zhang YY, Ye XM. Neurochem Int 67 9-13 (2014)
  41. P2 Purinergic Signaling in the Distal Lung in Health and Disease. Wirsching E, Fauler M, Fois G, Frick M. Int J Mol Sci 21 E4973 (2020)
  42. P2X7 receptor: a critical regulator and potential target for breast cancer. Zhu X, Li Q, Song W, Peng X, Zhao R. J Mol Med (Berl) 99 349-358 (2021)
  43. Perception of Damaged Self in Plants. Li Q, Wang C, Mou Z. Plant Physiol 182 1545-1565 (2020)
  44. Structural basis for the functional properties of the P2X7 receptor for extracellular ATP. Jiang LH, Caseley EA, Muench SP, Roger S. Purinergic Signal 17 331-344 (2021)
  45. Structural and Functional Basis for Understanding the Biological Significance of P2X7 Receptor. Martínez-Cuesta MÁ, Blanch-Ruiz MA, Ortega-Luna R, Sánchez-López A, Álvarez Á. Int J Mol Sci 21 E8454 (2020)
  46. Pleiotropic Roles of P2X7 in the Central Nervous System. Kanellopoulos JM, Delarasse C. Front Cell Neurosci 13 401 (2019)
  47. Post-translational regulation of P2X receptor channels: modulation by phospholipids. Bernier LP, Ase AR, Séguéla P. Front Cell Neurosci 7 226 (2013)
  48. Expression of P2 Purinergic Receptors in Mesenchymal Stem Cells and Their Roles in Extracellular Nucleotide Regulation of Cell Functions. Jiang LH, Hao Y, Mousawi F, Peng H, Yang X. J Cell Physiol 232 287-297 (2017)
  49. Implication of Neuronal Versus Microglial P2X4 Receptors in Central Nervous System Disorders. Duveau A, Bertin E, Boué-Grabot E. Neurosci Bull 36 1327-1343 (2020)
  50. Astroglial and Microglial Purinergic P2X7 Receptor as a Major Contributor to Neuroinflammation during the Course of Multiple Sclerosis. Sidoryk-Węgrzynowicz M, Strużyńska L. Int J Mol Sci 22 8404 (2021)
  51. Therapeutic Monoclonal Antibodies to Complex Membrane Protein Targets: Antigen Generation and Antibody Discovery Strategies. Dodd RB, Wilkinson T, Schofield DJ. BioDrugs 32 339-355 (2018)
  52. Ca2+ as a therapeutic target in cancer. Gross S, Mallu P, Joshi H, Schultz B, Go C, Soboloff J. Adv Cancer Res 148 233-317 (2020)
  53. Recommended tool compounds and drugs for blocking P2X and P2Y receptors. Müller CE, Namasivayam V. Purinergic Signal 17 633-648 (2021)
  54. Role of Neuroinflammation in the Trajectory of Alzheimer's Disease and in vivo Quantification Using PET. Edison P, Brooks DJ. J Alzheimers Dis 64 S339-S351 (2018)
  55. To Inhibit or Enhance? Is There a Benefit to Positive Allosteric Modulation of P2X Receptors? Stokes L, Bidula S, Bibič L, Allum E. Front Pharmacol 11 627 (2020)
  56. Regulation of ATP-gated P2X channels: from redox signaling to interactions with other proteins. Stojilkovic SS, Leiva-Salcedo E, Rokic MB, Coddou C. Antioxid Redox Signal 21 953-970 (2014)
  57. Purinergic P2X7 Receptor: A Cation Channel Sensitive to Tumor Microenvironment. Scarpellino G, Genova T, Munaron L. Recent Pat Anticancer Drug Discov 14 32-38 (2019)
  58. Purinergic signalling in autoimmunity: A role for the P2X7R in systemic lupus erythematosus? Di Virgilio F, Giuliani AL. Biomed J 39 326-338 (2016)
  59. Architectural and functional similarities between trimeric ATP-gated P2X receptors and acid-sensing ion channels. Kellenberger S, Grutter T. J Mol Biol 427 54-66 (2015)
  60. Molecular Structure and Regulation of P2X Receptors With a Special Emphasis on the Role of P2X2 in the Auditory System. Mittal R, Chan B, Grati M, Mittal J, Patel K, Debs LH, Patel AP, Yan D, Chapagain P, Liu XZ. J Cell Physiol 231 1656-1670 (2016)
  61. Novel approaches to drug design for the treatment of schizophrenia. Taly A. Expert Opin Drug Discov 8 1285-1296 (2013)
  62. Resolving the Ionotropic P2X4 Receptor Mystery Points Towards a New Therapeutic Target for Cardiovascular Diseases. Bragança B, Correia-de-Sá P. Int J Mol Sci 21 E5005 (2020)
  63. Effect of P2X purinergic receptors in tumor progression and as a potential target for anti-tumor therapy. Zhang WJ. Purinergic Signal 17 151-162 (2021)
  64. Purinergic control of inflammation and thrombosis: Role of P2X1 receptors. Oury C, Lecut C, Hego A, Wéra O, Delierneux C. Comput Struct Biotechnol J 13 106-110 (2015)
  65. Size matters in activation/inhibition of ligand-gated ion channels. Du J, Dong H, Zhou HX. Trends Pharmacol Sci 33 482-493 (2012)
  66. Alternatively Spliced Isoforms of the P2X7 Receptor: Structure, Function and Disease Associations. De Salis SKF, Li L, Chen Z, Lam KW, Skarratt KK, Balle T, Fuller SJ. Int J Mol Sci 23 8174 (2022)
  67. Enlightening activation gating in P2X receptors. Sattler C, Benndorf K. Purinergic Signal 18 177-191 (2022)
  68. Molecular Modeling Applied to the Discovery of New Lead Compounds for P2 Receptors Based on Natural Sources. Alberto AVP, da Silva Ferreira NC, Soares RF, Alves LA. Front Pharmacol 11 01221 (2020)
  69. P2X7 Receptor and Purinergic Signaling: Orchestrating Mitochondrial Dysfunction in Neurodegenerative Diseases. Zelentsova AS, Deykin AV, Soldatov VO, Ulezko AA, Borisova AY, Belyaeva VS, Skorkina MY, Angelova PR. eNeuro 9 ENEURO.0092-22.2022 (2022)
  70. P2X7 receptor-mediated TG2 externalization: a link to inflammatory arthritis? Aeschlimann D, Knäuper V. Amino Acids 49 453-460 (2017)
  71. Leveraging the ATP-P2X7 receptor signalling axis to alleviate traumatic CNS damage and related complications. Yin Y, Wei L, Caseley EA, Lopez-Charcas O, Wei Y, Li D, Muench SP, Roger S, Wang L, Jiang LH. Med Res Rev 43 1346-1373 (2023)
  72. P2X7 Receptor-Related Genetic Mouse Models - Tools for Translational Research in Psychiatry. Urbina-Treviño L, von Mücke-Heim IA, Deussing JM. Front Neural Circuits 16 876304 (2022)
  73. The P2 purinoceptors in prostate cancer. Wang Z, Zhu S, Tan S, Zeng Y, Zeng H. Purinergic Signal 19 255-263 (2023)
  74. Vas deferens neuro-effector junction: from kymographic tracings to structural biology principles. Navarrete LC, Barrera NP, Huidobro-Toro JP. Auton Neurosci 185 8-28 (2014)
  75. Purinergic signaling: Diverse effects and therapeutic potential in cancer. Kaur J, Dora S. Front Oncol 13 1058371 (2023)
  76. The P2X1 receptor as a therapeutic target. Bennetts FM, Mobbs JI, Ventura S, Thal DM. Purinergic Signal 18 421-433 (2022)
  77. A review of the pathophysiology and the role of ion channels on bronchial asthma. Figueiredo IAD, Ferreira SRD, Fernandes JM, Silva BAD, Vasconcelos LHC, Cavalcante FA. Front Pharmacol 14 1236550 (2023)
  78. P2 Receptors in Cardiac Myocyte Pathophysiology and Mechanotransduction. Woo SH, Trinh TN. Int J Mol Sci 22 E251 (2020)
  79. P2X7 Receptor: an Emerging Target in Alzheimer's Disease. Huang Q, Ying J, Yu W, Dong Y, Xiong H, Zhang Y, Liu J, Wang X, Hua F. Mol Neurobiol 61 2866-2880 (2024)
  80. P2Y Receptors in Bone - Anabolic, Catabolic, or Both? Zhou Y, Arredondo HM, Wang N. Front Endocrinol (Lausanne) 12 818499 (2021)
  81. Photopharmacology of Ion Channels through the Light of the Computational Microscope. Nin-Hill A, Mueller NPF, Molteni C, Rovira C, Alfonso-Prieto M. Int J Mol Sci 22 12072 (2021)
  82. Physiologic roles of P2 receptors in leukocytes. Alberto AVP, Ferreira NCDS, Bonavita AGC, Nihei OK, Farias FP, Bisaggio RDC, Albuquerque C, Savino W, Coutinho-Silva R, Persechini PM, Alves LA. J Leukoc Biol 112 983-1012 (2022)
  83. Untangling Macropore Formation and Current Facilitation in P2X7. Cevoli F, Arnould B, Peralta FA, Grutter T. Int J Mol Sci 24 10896 (2023)
  84. Screening Strategies for the Discovery of Ion Channel Monoclonal Antibodies. Colley CS, England E, Linley JE, Wilkinson TCI. Curr Protoc Pharmacol 82 e44 (2018)
  85. Pathophysiological Role of Purinergic P2X Receptors in Digestive System Diseases. An Q, Yue G, Yang X, Lou J, Shan W, Ding J, Jin Z, Hu Y, Du Q, Liao Q, Xie R, Xu J. Front Physiol 12 781069 (2021)
  86. Rehabilitation of the P2X5 receptor: a re-evaluation of structure and function. King BF. Purinergic Signal 19 421-439 (2023)
  87. Advances in Antibody-Based Therapeutics for Cerebral Ischemia. Sun JM, Yen TL, Jan JS, Mwale PF, Teng RD, Taliyan R, Hsieh CT, Yang CH. Pharmaceutics 15 145 (2022)
  88. Dilation of ion selectivity filters in cation channels. Huffer K, Tan XF, Fernández-Mariño AI, Dhingra S, Swartz KJ. Trends Biochem Sci 49 417-430 (2024)
  89. Ion channels in dry eye disease. Ashok N, Khamar P, D'Souza S, Gijs M, Ghosh A, Sethu S, Shetty R. Indian J Ophthalmol 71 1215-1226 (2023)
  90. Proteomic profiling of platelet signalling. Howes JM. Expert Rev Proteomics 10 355-364 (2013)
  91. Alternative Pharmacological Strategies for the Treatment of Alzheimer's Disease: Focus on Neuromodulator Function. Cunliffe G, Lim YT, Chae W, Jung S. Biomedicines 10 3064 (2022)
  92. Connexins, Pannexins and Gap Junctions in Perinatal Brain Injury. McDouall A, Zhou KQ, Bennet L, Green CR, Gunn AJ, Davidson JO. Biomedicines 10 1445 (2022)
  93. Functional role of P2X7 purinergic receptor in cancer and cancer-related pain. Xu YS, Xiang J, Lin SJ. Purinergic Signal (2024)
  94. P2X7 receptors: a bibliometric review from 2002 to 2023. Tang H, Wei W, Luo Y, Lu X, Chen J, Yang S, Wu F, Zhou H, Ma W, Yang X. Purinergic Signal (2024)
  95. Progress on functions of intracellular domain of trimeric ligand-gated ion channels. Lu Y, Lin Y, Wang J. Zhejiang Da Xue Xue Bao Yi Xue Ban 53 221-230 (2024)
  96. Unlocking the therapeutic potential of P2X7 receptor: a comprehensive review of its role in neurodegenerative disorders. Liu X, Li Y, Huang L, Kuang Y, Wu X, Ma X, Zhao B, Lan J. Front Pharmacol 15 1450704 (2024)

Articles citing this publication (156)



Quick links