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@ARTICLE{Cao:857528,
      author       = {Cao, Ruyin and Giorgetti, Alejandro and Bauer, Andreas and
                      Neumaier, Bernd and Rossetti, Giulia and Carloni, Paolo},
      title        = {{R}ole of {E}xtracellular {L}oops and {M}embrane {L}ipids
                      for {L}igand {R}ecognition in the {N}euronal {A}denosine
                      {R}eceptor {T}ype 2{A}: {A}n {E}nhanced {S}ampling
                      {S}imulation {S}tudy},
      journal      = {Molecules},
      volume       = {23},
      number       = {10},
      issn         = {1420-3049},
      address      = {Basel},
      publisher    = {MDPI75390},
      reportid     = {FZJ-2018-06519},
      pages        = {2616 -},
      year         = {2018},
      abstract     = {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.},
      cin          = {IAS-5 / INM-9 / INM-5 / INM-2 / JSC},
      ddc          = {540},
      cid          = {I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)INM-9-20140121 /
                      I:(DE-Juel1)INM-5-20090406 / I:(DE-Juel1)INM-2-20090406 /
                      I:(DE-Juel1)JSC-20090406},
      pnm          = {571 - Connectivity and Activity (POF3-571) / 511 -
                      Computational Science and Mathematical Methods (POF3-511)},
      pid          = {G:(DE-HGF)POF3-571 / G:(DE-HGF)POF3-511},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30322034},
      UT           = {WOS:000451201400212},
      doi          = {10.3390/molecules23102616},
      url          = {https://juser.fz-juelich.de/record/857528},
}