title: The Principles of Ligand Specificity on beta-2-adrenergic receptor.
abstract: G protein-coupled receptors are recognized as one of the largest families of membrane proteins. Despite sharing a characteristic seven-transmembrane topology, G protein-coupled receptors regulate a wide range of cellular signaling pathways in response to various physical and chemical stimuli, and prevail as an important target for drug discovery. Notably, the recent progress in crystallographic methods led to a breakthrough in elucidating the structures of membrane proteins. The structures of β2-adrenergic receptor bound with a variety of ligands provide atomic details of the binding modes of agonists, antagonists and inverse agonists. In this study, we selected four representative molecules from each functional class of ligands and investigated their impacts on β2-adrenergic receptor through a total of 12 × 100 ns molecular dynamics simulations. From the obtained trajectories, we generated molecular fingerprints exemplifying propensities of protein-ligand interactions. For each functional class of compounds, we characterized and compared the fluctuation of the protein backbone, the volumes in the intracellular pockets, the water densities in the receptors, the domain interaction networks as well as the movements of transmembrane helices. We discovered that each class of ligands exhibits a distinct mode of interactions with mainly TM5 and TM6, altering the shape and eventually the state of the receptor. Our findings provide insightful prospective into GPCR targeted structure-based drug discoveries.
authors.affiliation: Faculty of Life Sciences, University of Bradford, Bradford, West Yorkshire, BD7 1DP, United Kingdom.
authors.forename: H C Stephen
authors.initials: HC
authors.lastname: Chan
authors.affiliation: Laboratory of Biomodeling, Faculty of Chemistry &Biological and Chemical Research Centre, University of Warsaw, ul. Pasteura 1, Warsaw 02-093, Poland.
authors.forename: Slawomir
authors.initials: S
authors.lastname: Filipek
authors.affiliation: Laboratory of Physical Chemistry of Polymers and Membranes, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH B3 495 (Bâtiment CH) Station 6, Lausanne CH-1015, Switzerland.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Yuan
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000737:chemistry / Q000378:metabolism*; D058672:Adrenergic beta-2 Receptor Antagonists / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D025341:Principal Component Analysis; D011485:Protein Binding; D055550:Protein Stability; D017433:Protein Structure, Secondary; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C553443:ADRB2 protein, human; D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D008024:Ligands; D018343:Receptors, Adrenergic, beta-2