2011
DOI: 10.1073/pnas.1102170108
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Agonist trapped in ATP-binding sites of the P2X2 receptor

Abstract: ATP-gated P2X receptors are trimeric ion channels, as recently confirmed by X-ray crystallography. However, the structure was solved without ATP and even though extracellular intersubunit cavities surrounded by conserved amino acid residues previously shown to be important for ATP function were proposed to house ATP, the localization of the ATP sites remains elusive. Here we localize the ATP-binding sites by creating, through a proximity-dependent "tethering" reaction, covalent bonds between a synthesized ATPd… Show more

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Cited by 51 publications
(96 citation statements)
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References 33 publications
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“…For example, ATP binding to the cleft and subsequent cleft closure were predicted to occur based on proximity tethering (11), normal mode analysis (12), and both metal bridging and spectroscopic studies (13,14). In addition, the accessibility of both methanethiolsulfonate compounds and metals (Ag + and Cd 2+ ) to cysteine residues introduced into TM1 and TM2 (6)(7)(8) is consistent with the expansion of the external pore predicted from the zfP2X4 structures (Fig.…”
supporting
confidence: 60%
“…For example, ATP binding to the cleft and subsequent cleft closure were predicted to occur based on proximity tethering (11), normal mode analysis (12), and both metal bridging and spectroscopic studies (13,14). In addition, the accessibility of both methanethiolsulfonate compounds and metals (Ag + and Cd 2+ ) to cysteine residues introduced into TM1 and TM2 (6)(7)(8) is consistent with the expansion of the external pore predicted from the zfP2X4 structures (Fig.…”
supporting
confidence: 60%
“…3 B and C) revealed at least two poses that should allow the reaction with the side chain for all models except for the solvent-inaccessible E119C mutant and the A118C mutant, in which only one pose was identified. To further interpret our data, we measured the distance between the maleimide moiety of the docked TMRM and residue F188 (homologous to residue L186 in the P2X2R) as a marker for the ATP binding site (11). This measurement takes into account the flexibility of TMRM that should explore a cone in space after being fixed to the receptor and thus, gives a rough idea of possible interactions of TMRM with the ligands.…”
Section: Different Positions In the C1-c2 Intercysteine Stretch Sensementioning
confidence: 99%
“…Three of these disulfide bridges are arranged in the head domain (2). Two findings suggest a close association of this region with ATP binding: (i) the P2X7 subtype has been found to be constitutively active on ADP ribosylation of residue R125 located between the first and second conserved cysteine residues (10), and (ii) a recent report has shown that the thiol-reactive ATP analog 8-thiocyano-ATP (NCS-ATP) can be covalently attached to the cysteine-substituted residue N140C in the head domain of the P2X2R (11). To probe the proximity of the first intercysteine region to the presumed ATP binding site and a possible function of the cys-rich region in receptor activation and/or desensitization, we performed VCF with the fast desensitizing P2X1R expressed in Xenopus oocytes.…”
mentioning
confidence: 99%
“…For example, disulfide locking of pairs of engineered cysteine residues has provided direct evidence for the approximation of amino acid residues [32,[77][78][79][80][81][82][83][84]. The openclosed transition of the receptor can also be driven by light in the complete absence of ATP, when a light-sensitive azobenzene molecule is incorporated into the receptor by attachment to cysteine residues in two different subunits [85,86].…”
Section: Molecular Modus Operandimentioning
confidence: 99%