title: Identifying ligand binding conformations of the β2-adrenergic receptor by using its agonists as computational probes.
abstract: Recently available G-protein coupled receptor (GPCR) structures and biophysical studies suggest that the difference between the effects of various agonists and antagonists cannot be explained by single structures alone, but rather that the conformational ensembles of the proteins need to be considered. Here we use an elastic network model-guided molecular dynamics simulation protocol to generate an ensemble of conformers of a prototypical GPCR, β(2)-adrenergic receptor (β(2)AR). The resulting conformers are clustered into groups based on the conformations of the ligand binding site, and distinct conformers from each group are assessed for their binding to known agonists of β(2)AR. We show that the select ligands bind preferentially to different predicted conformers of β(2)AR, and identify a role of β(2)AR extracellular region as an allosteric binding site for larger drugs such as salmeterol. Thus, drugs and ligands can be used as "computational probes" to systematically identify protein conformers with likely biological significance.
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA. bai2@pitt.edu
authors.forename: Basak
authors.initials: B
authors.lastname: Isin
authors.forename: Guillermina
authors.initials: G
authors.lastname: Estiu
authors.forename: Olaf
authors.initials: O
authors.lastname: Wiest
authors.forename: Zoltán N
authors.initials: ZN
authors.lastname: Oltvai
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000378:metabolism*; D000420:Albuterol / Q000031:analogs & derivatives* / Q000378:metabolism; D000495:Allosteric Site; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D011487:Protein Conformation; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry* / Q000378:metabolism*; D000068299:Salmeterol Xinafoate; D013816:Thermodynamics
chemical_list: C553443:ADRB2 protein, human; D058666:Adrenergic beta-2 Receptor Agonists; D018343:Receptors, Adrenergic, beta-2; D000068299:Salmeterol Xinafoate; D000420:Albuterol