title: Predicting GPCR promiscuity using binding site features.
abstract: G protein-coupled receptors (GPCRs) represent a large family of signaling proteins that includes many therapeutic targets. GPCR ligands include odorants, tastants, and neurotransmitters and vary in size and properties. Dramatic chemical diversity may occur even among ligands of the same receptor. Our goal is to unravel the structural and chemical features that determine GPCRs' promiscuity toward their ligands. We perform statistical analysis using more than 30 descriptors related to the sequence, physicochemical, structural, and energetic properties of the GPCR binding sites-we find that the chemical variability of antagonists significantly correlates with the binding site hydrophobicity and anticorrelates with the number of hydrogen bond donors in the binding site. The number of disulfide bridges in the extracellular region of a receptor anticorrelates with the range of molecular weights of its antagonists, highlighting the role of the entrance pathway in determining the size selectivity for GPCR antagonists. The predictive capability of the model is successfully validated using a separate set of GPCRs, using either X-ray structures or homology models.
authors: Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture Food and Environment, The Hebrew University , Rehovot 76100, Israel.
authors: Anat
authors: A
authors: Levit
authors: Thijs
authors: T
authors: Beuming
authors: Goran
authors: G
authors: Krilov
authors: Woody
authors: W
authors: Sherman
authors: Masha Y
authors: MY
authors: Niv
mesh_terms: D000818:Animals; D001185:Artificial Intelligence; D001665:Binding Sites; D019295:Computational Biology; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D016018:Least-Squares Analysis; D008024:Ligands; D016014:Linear Models; D008958:Models, Molecular; D025341:Principal Component Analysis; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled