期刊
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
卷 35, 期 12, 页码 2604-2619出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/07391102.2016.1226197
关键词
GPCRs; beta adrenergic receptor; modelling; docking; active site pressurisation; molecular dynamics; protein flexibility
资金
- Royal Pharmaceutical Society
G protein-coupled receptors (GPCRs) are proteins of pharmaceutical importance, with over 30% of all drugs in clinical use targeting them. Increasing numbers of X-ray crystal (XRC) structures of GPCRs offer a wealth of data relating to ligand binding. For the -adrenoceptors (-ARs), XRC structures are available for human (2)- and turkey (1)-subtypes, in complexes with a range of ligands. While these structures provide insight into the origins of ligand structure-activity relationships (SARs), questions remain. The ligands in all published complexed XRC structures lack extensive substitution, with no obvious way the ligand-binding site can accommodate (1)-AR-selective antagonists with extended side-chains para- to the common aryloxypropanolamine pharmacophore. Using standard computational docking tools with such ligands generally returns poses that fail to explain known SARs. Application of our Active Site Pressurisation modelling method to -AR XRC structures and homology models, however, reveals a dynamic area in the ligand-binding pocket that, through minor changes in amino acid side chain orientations, opens a fissure between transmembrane helices H4 and H5, exposing intra-membrane space. This fissure, which we term the keyhole, is ideally located to accommodate extended moieties present in many high-affinity (1)-AR-selective ligands, allowing the rest of the ligand structure to adopt a canonical pose in the orthosteric binding site. We propose the keyhole may be a feature of both (1)- and (2)-ARs, but that subtle structural differences exist between the two, contributing to subtype-selectivity. This has consequences for the rational design of future generations of subtype-selective ligands for these therapeutically important targets.
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