Molecular dynamics simulation of the human adenosine A3 receptor: agonist induced conformational changes of Trp243

Hallmen, Christian; Wiese, Michael

doi:10.1007/s10822-006-9088-5

Cited by 24 publications

(26 citation statements)

References 37 publications

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“…The first MD simulation of an agonist-hA 3 AR complex embedded in a phospholipid bilayer [19] examined the conformational changes of conserved Trp243 (6.48). The study suggested that the agonist Cl-IB-MECA ( 9 ) but not the antagonist PBS-10 ( 21 ) stabilized the trans conformation of the Trp243 (6.48) residue, and that the conformational switch was presumably driven by a gain in the electrostatic interaction energy.…”

Section: Molecular Modeling Of the A3 Adenosine Receptormentioning

confidence: 99%

Structural Probing and Molecular Modeling of the A3 Adenosine Receptor: A Focus on Agonist Binding

Ciancetta

2017

Molecules

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Adenosine is an endogenous modulator exerting its functions through the activation of four adenosine receptor (AR) subtypes, termed A1, A2A, A2B and A3, which belong to the G protein-coupled receptor (GPCR) superfamily. The human A3AR (hA3AR) subtype is implicated in several cytoprotective functions. Therefore, hA3AR modulators, and in particular agonists, are sought for their potential application as anti-inflammatory, anticancer, and cardioprotective agents. Structure-based molecular modeling techniques have been applied over the years to rationalize the structure-activity relationships (SARs) of newly emerged A3AR ligands, guide the subsequent lead optimization, and interpret site-directed mutagenesis (SDM) data from a molecular perspective. In this review, we showcase selected modeling-based and guided strategies that were applied to elucidate the binding of agonists to the A3AR and discuss the challenges associated with an accurate prediction of the receptor extracellular vestibule through homology modeling from the available X-ray templates.

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Section: Molecular Modeling Of the A3 Adenosine Receptormentioning

confidence: 99%

Structural Probing and Molecular Modeling of the A3 Adenosine Receptor: A Focus on Agonist Binding

Ciancetta

2017

Molecules

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“…It was proposed [3,52] during MD simulation with no constraints of unliganded adenosine A 3 receptor (activation of this switch lasted about one nanosecond) as well as of its complex with an agonist (rotamer changed after about 2 ns and the switch continued to be activated) [54]. For the cannabinoid CB 1 receptor another type of rotamer toggle switch composed of W6.48 and located opposite F3.36 (which has an aromatic stacking interaction with W6.48) was proposed [55].…”

Section: Action Of the Rotamer Toggle Switch And Time Dependence Betwmentioning

confidence: 99%

Studies of the Activation Steps Concurrent to Ligand Binding in δOR and κOR Opioid Receptors Based on Molecular Dynamics Simulations

Koliński¹,

Filipek²

2009

TOSBJ

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Although agonists and antagonists occupy the same space in opioid receptors the agonists only are able to evoke their activation and different agonists may lead to different conformational states of the receptor. Agonist binding is the first step in ligand-induced receptor activation which proceeds through series of conformational changes. To investigate the relationship between the final movements of a ligand in a receptor binding site and the first steps of the activation process in OR and OR opioid receptors we chose a set of rigid ligands with the structural motif of tyramine. On the basis of conducted molecular dynamics simulations we propose that, similarly as in the case of μOR [Kolinski and Filipek, TOSBJ 2008], agonists and antagonists bind to Y3.33 but only agonists are able to move deeper into the receptor binding site and to reach H6.52. The movement from Y3.33 to H6.52 induces breaking of the TM3-TM7 connection ("3-7 lock"). However, conversely to morphine (previous paper) butorphanol did not induce breaking of this connection in a single movement but instead a time of about 20 ns was required and this process was composed of a series of separation and joining events. We also observed a concerted motion of W6.48 and H6.52 suggesting existence of an extended "rotamer toggle switch". Simultaneous action of both switches, the "3-7 lock" and the "rotamer toggle switch", implies a temporal but also spatial (an agonist linking H6.52 and D3.32) dependence between them.

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“…Additionally, Trp 243 has been shown to act as a switch in the TM6-mediated structural transition from the resting to the active state. [34] Interactions with the benzyl group of compound 10 with this residue would not allow the reorientation of its side chain accompanying the inactive to active state transition. Thus, this benzyl group would be responsible for the improved potency in the antagonistic effect of this family of compounds, in agreement with favorable van der Waals interactions with Trp 243.…”

Section: Molecular Modelingmentioning

confidence: 99%

Selective Human Adenosine A₃ Antagonists based on Pyrido[2,1‐f]purine‐2,4‐diones: Novel Features of hA₃ Antagonist Binding

et al. 2008

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Based on our previous results on the potent antagonist effect of 1H,3H-pyrido[2,1-f]purine-2,4-diones at the human A(3) adenosine receptor, new series of this family of compounds have been synthesized and evaluated in radioligand binding studies against the human A(1), A(2A), A(2B), and A(3) receptors. A remarkable improvement in potency, and most noticeable, in selectivity has been achieved, as exemplified by the 3-cyclopropylmethyl-8-methoxy-1-(4-methylbenzyl)-1H,3H-pyrido[2,1-f]purine-2,4-dione (10) that combines a very high affinity at hA(3) (K(i)=2.24 nM), with lack of affinity for the A(1), A(2A), and A(2B) receptors. On the basis of the published hA(3) receptor model (PDB 1OEA), molecular modeling studies, including molecular dynamics (MD) simulations, have been performed to depict the binding mode of the 1 H,3H-pyrido[2,1-f]purine-2,4-diones and to justify the selectivity against the other adenosine receptors. These studies have led to novel features of the cavity where our antagonists are bound so that the cavity is lined by the hydrogen-bonded Gln 167-Asn 250 pair and by the highly conserved Phe 168.

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Molecular dynamics simulation of the human adenosine A3 receptor: agonist induced conformational changes of Trp243

Cited by 24 publications

References 37 publications

Structural Probing and Molecular Modeling of the A3 Adenosine Receptor: A Focus on Agonist Binding

Structural Probing and Molecular Modeling of the A3 Adenosine Receptor: A Focus on Agonist Binding

Studies of the Activation Steps Concurrent to Ligand Binding in δOR and κOR Opioid Receptors Based on Molecular Dynamics Simulations

Selective Human Adenosine A₃ Antagonists based on Pyrido[2,1‐f]purine‐2,4‐diones: Novel Features of hA₃ Antagonist Binding

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Molecular dynamics simulation of the human adenosine A3 receptor: agonist induced conformational changes of Trp243

Cited by 24 publications

References 37 publications

Structural Probing and Molecular Modeling of the A3 Adenosine Receptor: A Focus on Agonist Binding

Structural Probing and Molecular Modeling of the A3 Adenosine Receptor: A Focus on Agonist Binding

Studies of the Activation Steps Concurrent to Ligand Binding in δOR and κOR Opioid Receptors Based on Molecular Dynamics Simulations

Selective Human Adenosine A3 Antagonists based on Pyrido[2,1‐f]purine‐2,4‐diones: Novel Features of hA3 Antagonist Binding

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Selective Human Adenosine A₃ Antagonists based on Pyrido[2,1‐f]purine‐2,4‐diones: Novel Features of hA₃ Antagonist Binding