Binding Interactions of Dopamine and Apomorphine in D2High and D2Low States of Human Dopamine D2 Receptor Using Computational and Experimental Techniques.
Identifieur interne : 000429 ( Main/Exploration ); précédent : 000428; suivant : 000430Binding Interactions of Dopamine and Apomorphine in D2High and D2Low States of Human Dopamine D2 Receptor Using Computational and Experimental Techniques.
Auteurs : Serdar Durdagi [Turquie] ; Ramin Ekhteiari Salmas [Turquie] ; Matthias Stein [Allemagne] ; Mine Yurtsever [Turquie] ; Philip SeemanSource :
- ACS chemical neuroscience [ 1948-7193 ] ; 2016.
English descriptors
- KwdEn :
- Apomorphine (metabolism), Apomorphine (pharmacology), Binding, Competitive (drug effects), Dopamine (metabolism), Dopamine (pharmacology), Dopamine Agonists (pharmacology), Dose-Response Relationship, Drug, Humans, Models, Molecular, Molecular Docking Simulation (methods), Protein Binding (drug effects), Protein Engineering, Receptors, Dopamine D2 (chemistry), Receptors, Dopamine D2 (drug effects), Receptors, Dopamine D2 (metabolism).
- MESH :
- chemical , chemistry : Receptors, Dopamine D2.
- chemical , drug effects : Receptors, Dopamine D2.
- chemical , metabolism : Apomorphine, Dopamine, Receptors, Dopamine D2.
- chemical , pharmacology : Apomorphine, Dopamine, Dopamine Agonists.
- drug effects : Binding, Competitive, Protein Binding.
- methods : Molecular Docking Simulation.
- Dose-Response Relationship, Drug, Humans, Models, Molecular, Protein Engineering.
Abstract
We have recently reported G-protein coupled receptor (GPCR) model structures for the active and inactive states of the human dopamine D2 receptor (D2R) using adrenergic crystal structures as templates. Since the therapeutic concentrations of dopamine agonists that suppress the release of prolactin are the same as those that act at the high-affinity state of the D2 receptor (D2High), D2High in the anterior pituitary gland is considered to be the functional state of the receptor. In addition, the therapeutic concentrations of anti-Parkinson drugs are also related to the dissociation constants in the D2High form of the receptor. The discrimination between the high- and low-affinity (D2Low) components of the D2R is not obvious and requires advanced computer-assisted structural biology investigations. Therefore, in this work, the derived D2High and D2Low receptor models (GPCR monomer and dimer three-dimensional structures) are used as drug-binding targets to investigate binding interactions of dopamine and apomorphine. The study reveals a match between the experimental dissociation constants of dopamine and apomorphine at their high- and low-affinity sites of the D2 receptor in monomer and dimer and their calculated dissociation constants. The allosteric receptor-receptor interaction for dopamine D2R dimer is associated with the accessibility of adjacent residues of transmembrane region 4. The measured negative cooperativity between agonist ligand at dopamine D2 receptor is also correctly predicted using the D2R homodimerization model.
DOI: 10.1021/acschemneuro.5b00271
PubMed: 26645629
Affiliations:
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Engineering</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">We have recently reported G-protein coupled receptor (GPCR) model structures for the active and inactive states of the human dopamine D2 receptor (D2R) using adrenergic crystal structures as templates. Since the therapeutic concentrations of dopamine agonists that suppress the release of prolactin are the same as those that act at the high-affinity state of the D2 receptor (D2High), D2High in the anterior pituitary gland is considered to be the functional state of the receptor. In addition, the therapeutic concentrations of anti-Parkinson drugs are also related to the dissociation constants in the D2High form of the receptor. The discrimination between the high- and low-affinity (D2Low) components of the D2R is not obvious and requires advanced computer-assisted structural biology investigations. Therefore, in this work, the derived D2High and D2Low receptor models (GPCR monomer and dimer three-dimensional structures) are used as drug-binding targets to investigate binding interactions of dopamine and apomorphine. The study reveals a match between the experimental dissociation constants of dopamine and apomorphine at their high- and low-affinity sites of the D2 receptor in monomer and dimer and their calculated dissociation constants. The allosteric receptor-receptor interaction for dopamine D2R dimer is associated with the accessibility of adjacent residues of transmembrane region 4. The measured negative cooperativity between agonist ligand at dopamine D2 receptor is also correctly predicted using the D2R homodimerization model.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>Turquie</li></country><region><li>Saxe-Anhalt</li></region><settlement><li>Magdebourg</li></settlement></list><tree><noCountry><name sortKey="Seeman, Philip" sort="Seeman, Philip" uniqKey="Seeman P" first="Philip" last="Seeman">Philip Seeman</name></noCountry><country name="Turquie"><noRegion><name sortKey="Durdagi, Serdar" sort="Durdagi, Serdar" uniqKey="Durdagi S" first="Serdar" last="Durdagi">Serdar Durdagi</name></noRegion><name sortKey="Salmas, Ramin Ekhteiari" sort="Salmas, Ramin Ekhteiari" uniqKey="Salmas R" first="Ramin Ekhteiari" last="Salmas">Ramin Ekhteiari Salmas</name><name sortKey="Yurtsever, Mine" sort="Yurtsever, Mine" uniqKey="Yurtsever M" first="Mine" last="Yurtsever">Mine Yurtsever</name></country><country name="Allemagne"><region name="Saxe-Anhalt"><name sortKey="Stein, Matthias" sort="Stein, Matthias" uniqKey="Stein M" first="Matthias" last="Stein">Matthias Stein</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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