This title appears in the Scientific Report :
2018
Please use the identifier:
http://hdl.handle.net/2128/20118 in citations.
Please use the identifier: http://dx.doi.org/10.3390/molecules23102616 in citations.
Role of Extracellular Loops and Membrane Lipids for Ligand Recognition in the Neuronal Adenosine Receptor Type 2A: An Enhanced Sampling Simulation Study
Role of Extracellular Loops and Membrane Lipids for Ligand Recognition in the Neuronal Adenosine Receptor Type 2A: An Enhanced Sampling Simulation Study
Human G-protein coupled receptors (GPCRs) are important targets for pharmaceutical intervention against neurological diseases. Here, we use molecular simulation to investigate the key step in ligand recognition governed by the extracellular domains in the neuronal adenosine receptor type 2A (hA2AR),...
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Personal Name(s): | Cao, Ruyin |
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Giorgetti, Alejandro / Bauer, Andreas / Neumaier, Bernd / Rossetti, Giulia (Corresponding author) / Carloni, Paolo | |
Contributing Institute: |
Computational Biomedicine; IAS-5 Jülich Supercomputing Center; JSC Molekulare Organisation des Gehirns; INM-2 Nuklearchemie; INM-5 Computational Biomedicine; INM-9 |
Published in: | Molecules, 23 (2018) 10, S. 2616 - |
Imprint: |
Basel
MDPI75390
2018
|
DOI: |
10.3390/molecules23102616 |
PubMed ID: |
30322034 |
Document Type: |
Journal Article |
Research Program: |
Computational Science and Mathematical Methods Connectivity and Activity |
Link: |
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Publikationsportal JuSER |
Please use the identifier: http://dx.doi.org/10.3390/molecules23102616 in citations.
Human G-protein coupled receptors (GPCRs) are important targets for pharmaceutical intervention against neurological diseases. Here, we use molecular simulation to investigate the key step in ligand recognition governed by the extracellular domains in the neuronal adenosine receptor type 2A (hA2AR), a target for neuroprotective compounds. The ligand is the high-affinity antagonist (4-(2-(7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-ylamino)ethyl)phenol), embedded in a neuronal membrane mimic environment. Free energy calculations, based on well-tempered metadynamics, reproduce the experimentally measured binding affinity. The results are consistent with the available mutagenesis studies. The calculations identify a vestibular binding site, where lipids molecules can actively participate to stabilize ligand binding. Bioinformatic analyses suggest that such vestibular binding site and, in particular, the second extracellular loop, might drive the ligand toward the orthosteric binding pocket, possibly by allosteric modulation. Taken together, these findings point to a fundamental role of the interaction between extracellular loops and membrane lipids for ligands’ molecular recognition and ligand design in hA2AR. |