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Molecular determinants for agonist recognition and discrimination in P2X2 receptors
- Source :
- Gasparri, F, Wengel, J, Grutter, T & Pless, S A 2019, ' Molecular determinants for agonist recognition and discrimination in P2X2 receptors ', Journal of General Physiology, vol. 151, no. 7, pp. 898–911 . https://doi.org/10.1085/jgp.201912347, Journal of General Physiology, Journal of General Physiology, Rockefeller University Press, 2019, 151 (7), pp.898-911. ⟨10.1085/jgp.201912347⟩, The Journal of General Physiology, Gasparri, F, Wengel, J, Grutter, T & Pless, S A 2019, ' Molecular determinants for agonist recognition and discrimination in P2X2 receptors ', Journal of General Physiology, vol. 151, no. 7, pp. 898-911 . https://doi.org/10.1085/jgp.201912347
- Publication Year :
- 2019
-
Abstract
- P2X receptors (P2XRs) are ligand-gated cation channels involved in pain and inflammation. Gasparri et al. show that the backbone carbonyl atoms of amino acid residue Thr184 are involved in ligand discrimination, while those of Lys69 contribute mostly to ligand recognition by rat P2X2Rs.<br />P2X receptors (P2XRs) are trimeric ligand-gated ion channels that open a cation-selective pore in response to ATP binding. P2XRs contribute to synaptic transmission and are involved in pain and inflammation, thus representing valuable drug targets. Recent crystal structures have confirmed the findings of previous studies with regards to the amino acid chains involved in ligand recognition, but they have also suggested that backbone carbonyl atoms contribute to ATP recognition and discrimination. Here we use a combination of site-directed mutagenesis, amide-to-ester substitutions, and a range of ATP analogues with subtle alterations to either base or sugar component to investigate the contributions of backbone carbonyl atoms toward ligand recognition and discrimination in rat P2X2Rs. Our findings demonstrate that while the Lys69 backbone carbonyl makes an important contribution to ligand recognition, the discrimination between different ligands is mediated by both the side chain and the backbone carbonyl oxygen of Thr184. Together, our data demonstrate how conserved elements in P2X2Rs recognize and discriminate agonists.
- Subjects :
- 0301 basic medicine
Agonist
Physiology
Stereochemistry
medicine.drug_class
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
Plasma protein binding
Purinergic P2X Receptor Agonists
03 medical and health sciences
Xenopus laevis
0302 clinical medicine
Side chain
medicine
Animals
Humans
Binding site
Receptor
Ion channel
Research Articles
ComputingMilieux_MISCELLANEOUS
chemistry.chemical_classification
Binding Sites
Ligand
3. Good health
Amino acid
[SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics
030104 developmental biology
HEK293 Cells
chemistry
Amino Acid Substitution
030217 neurology & neurosurgery
Protein Binding
Receptors, Purinergic P2X2
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 00221295 and 15407748
- Database :
- OpenAIRE
- Journal :
- Gasparri, F, Wengel, J, Grutter, T & Pless, S A 2019, ' Molecular determinants for agonist recognition and discrimination in P2X2 receptors ', Journal of General Physiology, vol. 151, no. 7, pp. 898–911 . https://doi.org/10.1085/jgp.201912347, Journal of General Physiology, Journal of General Physiology, Rockefeller University Press, 2019, 151 (7), pp.898-911. ⟨10.1085/jgp.201912347⟩, The Journal of General Physiology, Gasparri, F, Wengel, J, Grutter, T & Pless, S A 2019, ' Molecular determinants for agonist recognition and discrimination in P2X2 receptors ', Journal of General Physiology, vol. 151, no. 7, pp. 898-911 . https://doi.org/10.1085/jgp.201912347
- Accession number :
- edsair.doi.dedup.....0fb8ad2e671cf38f7cf689f42f67b85a