Comparative models of P2X2 receptor support inter-subunit ATP-binding sites |
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Authors: | Guerlet Guillaume Taly Antoine Prado de Carvalho Lia Martz Adeline Jiang Ruotian Specht Alexandre Le Novère Nicolas Grutter Thomas |
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Institution: | a Department of Bioorganic Chemistry, UMR 7175 CNRS, Faculté de Pharmacie, Université Louis Pasteur, 67401 Illkirch, France b UMR 7006, ISIS, Université Louis Pasteur, Strasbourg, France c EMBL-EBI, Hinxton, EBI, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK |
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Abstract: | ATP-gated P2X receptors (P2XRs) are ligand-gated ion channels (LGICs) presumably trimeric. To date, no experimental high-resolution structures are available. Recent X-ray structure of the acid-sensing ion channel 1 (ASIC1) revealed an unexpected trimeric ion channel. Beside their quaternary structure, P2XR and ASIC1 share common membrane topologies, but no significant sequence similarity. In order to overcome this low sequence resemblance, we have developed comparative models of P2X2R based on secondary structure predictions using the crystal structure of ASIC1 as template. These models were constrained to be consistent with known arrangement of disulfide bridges. They agreed with cross-linking experiments and supported inter-subunit ATP-binding sites. One of our models reconciled most existing data and provides new structural insights for a plausible mechanism of gating, thus encouraging new experiments. |
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Keywords: | Ligand-gated ion channel P2X receptor ATP Purinergic Gating ASIC Comparative modeling Secondary structure predictions |
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