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000857528 1001_ $$0P:(DE-Juel1)168598$$aCao, Ruyin$$b0
000857528 245__ $$aRole of Extracellular Loops and Membrane Lipids for Ligand Recognition in the Neuronal Adenosine Receptor Type 2A: An Enhanced Sampling Simulation Study
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000857528 520__ $$aHuman G-protein coupled receptors (GPCRs) are important targets for pharmaceutical intervention against neurological diseases. Here, we use molecular simulation to investigate the key step in ligand recognition governed by the extracellular domains in the neuronal adenosine receptor type 2A (hA2AR), a target for neuroprotective compounds. The ligand is the high-affinity antagonist (4-(2-(7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-ylamino)ethyl)phenol), embedded in a neuronal membrane mimic environment. Free energy calculations, based on well-tempered metadynamics, reproduce the experimentally measured binding affinity. The results are consistent with the available mutagenesis studies. The calculations identify a vestibular binding site, where lipids molecules can actively participate to stabilize ligand binding. Bioinformatic analyses suggest that such vestibular binding site and, in particular, the second extracellular loop, might drive the ligand toward the orthosteric binding pocket, possibly by allosteric modulation. Taken together, these findings point to a fundamental role of the interaction between extracellular loops and membrane lipids for ligands’ molecular recognition and ligand design in hA2AR.
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000857528 7001_ $$0P:(DE-Juel1)165199$$aGiorgetti, Alejandro$$b1$$ufzj
000857528 7001_ $$0P:(DE-Juel1)131672$$aBauer, Andreas$$b2$$ufzj
000857528 7001_ $$0P:(DE-Juel1)166419$$aNeumaier, Bernd$$b3$$ufzj
000857528 7001_ $$0P:(DE-Juel1)145921$$aRossetti, Giulia$$b4$$eCorresponding author
000857528 7001_ $$0P:(DE-Juel1)145614$$aCarloni, Paolo$$b5$$ufzj
000857528 773__ $$0PERI:(DE-600)2008644-1$$a10.3390/molecules23102616$$gVol. 23, no. 10, p. 2616 -$$n10$$p2616 -$$tMolecules$$v23$$x1420-3049$$y2018
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