ArticleProceedings of the National Academy of Sciences of the United States of America2012
Gating mechanism of a P2X4 receptor developed from normal mode analysis and molecular dynamics simulations.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 54 citations in OpenAlex.
- Enlightening activation gating in P2X receptors.Purinergic signalling · 2022Review
- Modulation of P2X4 pore closure by magnesium, potassium, and ATP.Biophysical journal · 2022Article
- Unravelling the intricate cooperativity of subunit gating in P2X2 ion channels.Scientific reports · 2020Article
- Role of Conserved Residues and F322 in the Extracellular Vestibule of the Rat P2X7 Receptor in Its Expression, Function and Dye Uptake Ability.International journal of molecular sciences · 2020Article
- Toward a Model for Activation of Orai Channel.iScience · 2019Article
- Exploring conformational states and helical packings in the P2X receptor transmembrane domain by molecular dynamics simulation.Journal of biological physics · 2018Article
- P2X4: A fast and sensitive purinergic receptor.Biomedical journal · 2017Review
- Intersubunit physical couplings fostered by the left flipper domain facilitate channel opening of P2X4 receptors.The Journal of biological chemistry · 2017Article
- Gating Motions and Stationary Gating Properties of Ionotropic Glutamate Receptors: Computation Meets Electrophysiology.Accounts of chemical research · 2017Review
- The Dynamic Behavior of the P2XBiophysical journal · 2016Article
- Inter-subunit disulfide locking of the human P2X3 receptor elucidates ectodomain movements associated with channel gating.Purinergic signalling · 2016Article
- Photo-switchable tweezers illuminate pore-opening motions of an ATP-gated P2X ion channel.eLife · 2016Article
- Insights into the channel gating of P2X receptors from structures, dynamics and small molecules.Acta pharmacologica Sinica · 2016Review
- Roles of the lateral fenestration residues of the P2X₄ receptor that contribute to the channel function and the deactivation effect of ivermectin.Purinergic signalling · 2015Article
- A combined coarse-grained and all-atom simulation of TRPV1 channel gating and heat activation.The Journal of general physiology · 2015Article
- Article
- Inherent dynamics of head domain correlates with ATP-recognition of P2X4 receptors: insights gained from molecular simulations.PloS one · 2014Article
- Exploring the ATP-binding site of P2X receptors.Frontiers in cellular neuroscience · 2013Review
- Heteromeric assembly of P2X subunits.Frontiers in cellular neuroscience · 2013Review
- Post-translational regulation of P2X receptor channels: modulation by phospholipids.Frontiers in cellular neuroscience · 2013Review
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
P2X receptors are trimeric ATP-gated cation channels participating in diverse physiological processes. How ATP binding triggers channel opening remains unclear. Here the gating mechanism of a P2X receptor was studied by normal mode analysis and molecular dynamics (MD) simulations. Based on the resting-state crystal structure, a normal mode involving coupled motions of three β-strands (β1, β13, and β14) at the trimeric interface of the ligand-binding ectodomain and the pore-lining helix (TM2) in the transmembrane domain (TMD) was identified. The resulting widening of the fenestrations above the TMD and opening of the transmembrane pore produce known signatures of channel activation. In MD simulations, ATP was initially placed in the putative binding pocket (defined by four charged residues located in β1, β13 and β14) in two opposite orientations, with the adenine either proximal or distal to the TMD. In the proximal orientation, the triphosphate group extends outward to draw in the four charged residues, leading to closure of β13/β14 toward β1. The adenine ring, wedged between β1 and β13, acts as a fulcrum for the β14 lever, turning a modest closure around the triphosphate group into significant opening of the pre-TM2 loop. The motions of these β-strands are similar to those in the putative channel-activation normal mode. In the distal orientation, the ATP stabilizes the trimeric interface and the closure of the pre-TM2 loop, possibly representing desensitization. Our computational studies produced the first complete model, supported by experimental data, for how ATP binding triggers activation of a P2X receptor.
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