Home LiteratureArticle Details
PMID: 18247022 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Review

Orthosteric and allosteric binding sites of P2X receptors.

European biophysics journal : EBJ ·Vol. 38 ·No. 3 ·2009-03-00 ·Pages 319-27

Evans RJ

Abstract

P2X receptors for ATP comprise a distinct family of ligand gated ion channels with a range of properties. They have been shown to be involved in a variety of physiological processes including blood clotting, sensory perception, pain sensation, bone formation as well as inflammation and may provide a number of novel drug targets. In addition to the orthosteric site for ATP binding it has been suggested that there may be additional allosteric sites that regulate agonist action at the receptor. There is currently no crystal structure available for P2X receptors and the lack of sequence similarity to other ATP binding proteins has meant that a mutagenesis-based approach has been used primarily to investigate receptor structure-function. This review aims to provide an overview of recent work that gives an insight into residues involved in ATP action and allosteric regulation.

MeSH Terms
Adenosine Triphosphate/metabolism Allosteric Site Amino Acid Sequence Animals Binding Sites Humans Ion Channel Gating/physiology Models, Molecular Molecular Sequence Data Protein Conformation Receptors, Purinergic P2/physiology Receptors, Purinergic P2X
Chemicals
Receptors, Purinergic P2 Receptors, Purinergic P2X Adenosine Triphosphate
Authors & Affiliations
1 authors, click to expand affiliations / ORCID
Evans R J
Department of Cell Physiology and Pharmacology, University of Leicester, Leicester LE19HN, UK. rje6@le.ac.uk
References (61)
61 references, click to expand
  1. ATP-activated channels in rat and bullfrog sensory neurons: concentration dependence and kinetics.
    J Neurosci. 1990 Jan;10(1):1-10 PMID: 1688928
  2. Crystal structure of an inactive duck delta II crystallin mutant with bound argininosuccinate.
    Biochemistry. 1999 Feb 23;38(8):2425-34 PMID: 10029536
  3. Contribution of conserved glycine residues to ATP action at human P2X1 receptors: mutagenesis indicates that the glycine at position 250 is important for channel function.
    J Neurochem. 2005 Dec;95(6):1746-54 PMID: 16236030
  4. The role of histidine residues in modulation of the rat P2X(2) purinoceptor by zinc and pH.
    J Physiol. 2002 Mar 1;539(Pt 2):347-59 PMID: 11882669
  5. Mutational analysis of the conserved cysteines of the rat P2X2 purinoceptor.
    J Neurosci. 2002 May 15;22(10):3873-80 PMID: 12019306
  6. Crystal structure of bovine Cu,Zn superoxide dismutase at 3 A resolution: chain tracing and metal ligands.
    Proc Natl Acad Sci U S A. 1975 Apr;72(4):1349-53 PMID: 1055410
  7. Thr339-to-serine substitution in rat P2X2 receptor second transmembrane domain causes constitutive opening and indicates a gating role for Lys308.
    J Neurosci. 2007 Nov 21;27(47):12916-23 PMID: 18032665
  8. Mutagenesis studies of conserved proline residues of human P2X receptors for ATP indicate that proline 272 contributes to channel function.
    J Neurochem. 2005 Mar;92(5):1256-64 PMID: 15715674
  9. Identification of amino acid residues contributing to the ATP-binding site of a purinergic P2X receptor.
    J Biol Chem. 2000 Nov 3;275(44):34190-6 PMID: 10940304
  10. Zn2+ potentiates ATP-activated currents in rat sympathetic neurons.
    Pflugers Arch. 1993 Jul;424(2):152-8 PMID: 7692385
  11. Conserved cysteine residues in the extracellular loop of the human P2X(1) receptor form disulfide bonds and are involved in receptor trafficking to the cell surface.
    Mol Pharmacol. 2002 Feb;61(2):303-11 PMID: 11809854
  12. Lack of evidence for functional ADP-activated human P2X1 receptors supports a role for ATP during hemostasis and thrombosis.
    Blood. 2003 Nov 15;102(10):3646-51 PMID: 12907444
  13. The role of positively charged amino acids in ATP recognition by human P2X(1) receptors.
    J Biol Chem. 2000 Sep 22;275(38):29361-7 PMID: 10827197
  14. Histidine 140 plays a key role in the inhibitory modulation of the P2X4 nucleotide receptor by copper but not zinc.
    J Biol Chem. 2003 Sep 19;278(38):36777-85 PMID: 12819199
  15. Molecular properties of ATP-gated P2X receptor ion channels.
    Trends Pharmacol Sci. 2004 Sep;25(9):487-93 PMID: 15559251
  16. Different sensitivities to pH of ATP-induced currents at four cloned P2X receptors.
    J Neurophysiol. 1997 Oct;78(4):1837-40 PMID: 9325352
  17. ADP-ribosylation at R125 gates the P2X7 ion channel by presenting a covalent ligand to its nucleotide binding site.
    FASEB J. 2008 Mar;22(3):861-9 PMID: 17928361
  18. A histidine scan to probe the flexibility of the rat P2X2 receptor zinc-binding site.
    J Biol Chem. 2007 Jul 6;282(27):19526-33 PMID: 17517890
  19. Participation of the Lys313-Ile333 sequence of the purinergic P2X4 receptor in agonist binding and transduction of signals to the channel gate.
    J Biol Chem. 2006 Oct 27;281(43):32649-59 PMID: 16954225
  20. Single channel properties of P2X2 purinoceptors.
    J Gen Physiol. 1999 May;113(5):695-720 PMID: 10228183
  21. Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH.
    Nature. 2007 Sep 20;449(7160):316-23 PMID: 17882215
  22. Distantly related sequences in the alpha- and beta-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold.
    EMBO J. 1982;1(8):945-51 PMID: 6329717
  23. Effects of diadenosine polyphosphates (Ap(n)As) and adenosine polyphospho guanosines (Ap(n)Gs) on rat mesenteric artery P2X receptor ion channels.
    Br J Pharmacol. 2000 Jan;129(1):124-30 PMID: 10694211
  24. An intersubunit zinc binding site in rat P2X2 receptors.
    J Biol Chem. 2005 Jul 15;280(28):25982-93 PMID: 15899882
  25. Binding, gating, affinity and efficacy: the interpretation of structure-activity relationships for agonists and of the effects of mutating receptors.
    Br J Pharmacol. 1998 Nov;125(5):924-47 PMID: 9846630
  26. Differential modulation by copper and zinc of P2X2 and P2X4 receptor function.
    J Neurophysiol. 1999 May;81(5):2088-94 PMID: 10322050
  27. Identification of an intersubunit cross-link between substituted cysteine residues located in the putative ATP binding site of the P2X1 receptor.
    J Neurosci. 2007 Feb 7;27(6):1456-66 PMID: 17287520
  28. Contribution of conserved polar glutamine, asparagine and threonine residues and glycosylation to agonist action at human P2X1 receptors for ATP.
    J Neurochem. 2006 Feb;96(3):843-52 PMID: 16371009
  29. Identification of key residues coordinating functional inhibition of P2X7 receptors by zinc and copper.
    Mol Pharmacol. 2008 Jan;73(1):252-9 PMID: 17959713
  30. Molecular properties of P2X receptors.
    Pflugers Arch. 2006 Aug;452(5):486-500 PMID: 16607539
  31. Effects of divalent cations, protons and calmidazolium at the rat P2X7 receptor.
    Neuropharmacology. 1997 Sep;36(9):1285-94 PMID: 9364483
  32. Role of aromatic and charged ectodomain residues in the P2X(4) receptor functions.
    J Neurochem. 2007 Aug;102(4):1139-50 PMID: 17663752
  33. Cysteine substitution mutants give structural insight and identify ATP binding and activation sites at P2X receptors.
    J Neurosci. 2007 Apr 11;27(15):4072-82 PMID: 17428985
  34. Molecular dissection of purinergic P2X receptor channels.
    Ann N Y Acad Sci. 2005 Jun;1048:116-30 PMID: 16154926
  35. An intracellular P2X receptor required for osmoregulation in Dictyostelium discoideum.
    Nature. 2007 Jul 12;448(7150):200-3 PMID: 17625565
  36. Role of ectodomain lysines in the subunits of the heteromeric P2X2/3 receptor.
    Mol Pharmacol. 2006 Oct;70(4):1159-63 PMID: 16840712
  37. NAD-induced T cell death: ADP-ribosylation of cell surface proteins by ART2 activates the cytolytic P2X7 purinoceptor.
    Immunity. 2003 Oct;19(4):571-82 PMID: 14563321
  38. Conserved negatively charged residues are not required for ATP action at P2X(1) receptors.
    Biochem Biophys Res Commun. 2001 Dec 7;289(3):700-4 PMID: 11726204
  39. Molecular physiology of P2X receptors.
    Physiol Rev. 2002 Oct;82(4):1013-67 PMID: 12270951
  40. Zinc and copper modulate differentially the P2X4 receptor.
    J Neurochem. 2000 Apr;74(4):1529-37 PMID: 10737610
  41. Extracellular histidine residues identify common structural determinants in the copper/zinc P2X2 receptor modulation.
    J Neurochem. 2005 Oct;95(2):499-512 PMID: 16190872
  42. Pharmacology of cloned P2X receptors.
    Annu Rev Pharmacol Toxicol. 2000;40:563-80 PMID: 10836147
  43. Proton potentiation of ATP-gated ion channel responses to ATP and Zn2+ in rat nodose ganglion neurons.
    J Neurophysiol. 1996 Nov;76(5):3048-58 PMID: 8930254
  44. Identification of amino acid residues contributing to the pore of a P2X receptor.
    EMBO J. 1997 Jun 16;16(12):3446-54 PMID: 9218787
  45. Amino acid residues involved in gating identified in the first membrane-spanning domain of the rat P2X(2) receptor.
    J Biol Chem. 2001 May 4;276(18):14902-8 PMID: 11278888
  46. Dissecting the facilitator and inhibitor allosteric metal sites of the P2X4 receptor channel: critical roles of CYS132 for zinc potentiation and ASP138 for copper inhibition.
    J Biol Chem. 2007 Dec 21;282(51):36879-86 PMID: 17962187
  47. Mutation of histidine 286 of the human P2X4 purinoceptor removes extracellular pH sensitivity.
    J Physiol. 2000 Mar 15;523 Pt 3:697-703 PMID: 10718748
  48. Protein consensus sequence motifs.
    Mol Biotechnol. 1999 Oct;12(3):241-53 PMID: 10631681
  49. A novel neuronal P2x ATP receptor ion channel with widespread distribution in the brain.
    J Neurosci. 1996 Jan 15;16(2):448-55 PMID: 8551329
  50. ATP binding at human P2X1 receptors. Contribution of aromatic and basic amino acids revealed using mutagenesis and partial agonists.
    J Biol Chem. 2004 Mar 5;279(10):9043-55 PMID: 14699168
  51. ADP is not an agonist at P2X(1) receptors: evidence for separate receptors stimulated by ATP and ADP on human platelets.
    Br J Pharmacol. 2000 Sep;131(1):108-14 PMID: 10960076
  52. Dual effect of acid pH on purinergic P2X3 receptors depends on the histidine 206 residue.
    J Biol Chem. 2007 Nov 23;282(47):33949-57 PMID: 17890225
  53. Molecular determinants of the agonist binding domain of a P2X receptor channel.
    Mol Pharmacol. 2005 Apr;67(4):1078-88 PMID: 15632318
  54. Modulatory activity of extracellular H+ and Zn2+ on ATP-responses at rP2X1 and rP2X3 receptors.
    Br J Pharmacol. 1999 Sep;128(2):486-92 PMID: 10510462
  55. P2X4: an ATP-activated ionotropic receptor cloned from rat brain.
    Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3684-8 PMID: 8622997
  56. Full sensitivity of P2X2 purinoceptor to ATP revealed by changing extracellular pH.
    Br J Pharmacol. 1996 Apr;117(7):1371-3 PMID: 8730726
  57. New structural motif for ligand-gated ion channels defined by an ionotropic ATP receptor.
    Nature. 1994 Oct 6;371(6497):519-23 PMID: 7523952
  58. Differential role of extracellular histidines in copper, zinc, magnesium and proton modulation of the P2X7 purinergic receptor.
    J Neurochem. 2007 Apr;101(1):17-26 PMID: 17394459
  59. Zn2+ modulation of ATP-responses at recombinant P2X2 receptors and its dependence on extracellular pH.
    Br J Pharmacol. 1998 Mar;123(6):1214-20 PMID: 9559907
  60. Properties of ATP-gated channels recorded from rat sympathetic neurons: voltage dependence and regulation by Zn2+ ions.
    J Neurophysiol. 1995 Jan;73(1):312-9 PMID: 7714574
  61. Zn2+ potentiates excitatory action of ATP on mammalian neurons.
    Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):8264-7 PMID: 7690146
Article Info
Journal
European biophysics journal : EBJ
Abbr.
Eur Biophys J
ISSN
1432-1017
DOI
10.1007/s00249-008-0275-2
Email
rje6@le.ac.uk
Published
2009-03-00
Epub
2008-00-05
Pages
319-27
Language
English
Region
Germany
NLM ID
8409413
Subset
IM
Grants
British Heart Foundation · United Kingdom
Wellcome Trust · United Kingdom
External Links
PubMed source DOI: 10.1007/s00249-008-0275-2 View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2