ArticlePloS one2014
Inherent dynamics of head domain correlates with ATP-recognition of P2X4 receptors: insights gained from molecular simulations.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 34 citations in OpenAlex.
- Bayesian inference of functional asymmetry in the homotrimeric ligand-gated ion channel P2XCommunications biology · 2025Article
- Species Differences of P2X4 Receptor Modulators.ACS pharmacology & translational science · 2025Article
- Modulation of P2X4 pore closure by magnesium, potassium, and ATP.Biophysical journal · 2022Article
- GSK1702934A and M085 directly activate TRPC6 via a mechanism of stimulating the extracellular cavity formed by the pore helix and transmembrane helix S6.The Journal of biological chemistry · 2021Article
- Therapeutic inhibition of keratinocyte TRPV3 sensory channel by local anesthetic dyclonine.eLife · 2021Article
- Altered allostery of the left flipper domain underlies the weak ATP response of rat P2X5 receptors.The Journal of biological chemistry · 2019Article
- Druggable negative allosteric site of P2X3 receptors.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Intersubunit physical couplings fostered by the left flipper domain facilitate channel opening of P2X4 receptors.The Journal of biological chemistry · 2017Article
- 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
- A Highly Conserved Salt Bridge Stabilizes the Kinked Conformation of β2,3-Sheet Essential for Channel Function of P2X4 Receptors.The Journal of biological chemistry · 2016Article
- Exploration of the Peptide Recognition of an Amiloride-sensitive FMRFamide Peptide-gated Sodium Channel.The Journal of biological chemistry · 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
- Key sites for P2X receptor function and multimerization: overview of mutagenesis studies on a structural basis.Current medicinal chemistry · 2015Review
- Non-synonymous single nucleotide polymorphisms in the P2X receptor genes: association with diseases, impact on receptor functions and potential use as diagnosis biomarkers.International journal of molecular sciences · 2014Review
- Article
- A conserved residue in the P2X4 receptor has a nonconserved function in ATP recognition.The Journal of biological chemistryArticle
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
P2X receptors are ATP-gated ion channels involved in many physiological functions, and determination of ATP-recognition (AR) of P2X receptors will promote the development of new therapeutic agents for pain, inflammation, bladder dysfunction and osteoporosis. Recent crystal structures of the zebrafish P2X4 (zfP2X4) receptor reveal a large ATP-binding pocket (ABP) located at the subunit interface of zfP2X4 receptors, which is occupied by a conspicuous cluster of basic residues to recognize triphosphate moiety of ATP. Using the engineered affinity labeling and molecular modeling, at least three sites (S1, S2 and S3) within ABP have been identified that are able to recognize the adenine ring of ATP, implying the existence of at least three distinct AR modes in ABP. The open crystal structure of zfP2X4 confirms one of three AR modes (named AR1), in which the adenine ring of ATP is buried into site S1 while the triphosphate moiety interacts with clustered basic residues. Why architecture of ABP favors AR1 not the other two AR modes still remains unexplored. Here, we examine the potential role of inherent dynamics of head domain, a domain involved in ABP formation, in AR determinant of P2X4 receptors. In silico docking and binding free energy calculation revealed comparable characters of three distinct AR modes. Inherent dynamics of head domain, especially the downward motion favors the preference of ABP for AR1 rather than AR2 and AR3. Along with the downward motion of head domain, the closing movement of loop139-146 and loop169-183, and structural rearrangements of K70, K72, R298 and R143 enabled ABP to discriminate AR1 from other AR modes. Our observations suggest the essential role of head domain dynamics in determining AR of P2X4 receptors, allowing evaluation of new strategies aimed at developing specific blockers/allosteric modulators by preventing the dynamics of head domain associated with both AR and channel activation of P2X4 receptors.
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