title: Structure-Based Understanding of Binding Affinity and Mode of Estrogen Receptor α Agonists and Antagonists.
abstract: The flexible hydrophobic ligand binding pocket (LBP) of estrogen receptor α (ERα) allows the binding of a wide variety of endocrine disruptors. Upon ligand binding, the LBP reshapes around the contours of the ligand and stabilizes the complex by complementary hydrophobic interactions and specific hydrogen bonds with the ligand. Here we present a framework for quantitative analysis of the steric and electronic features of the human ERα-ligand complex using three dimensional (3D) protein-ligand interaction description combined with 3D-QSAR approach. An empirical hydrophobicity density field is applied to account for hydrophobic contacts of ligand within the LBP. The obtained 3D-QSAR model revealed that hydrophobic contacts primarily determine binding affinity and govern binding mode with hydrogen bonds. Several residues of the LBP appear to be quite flexible and adopt a spectrum of conformations in various ERα-ligand complexes, in particular His524. The 3D-QSAR was combined with molecular docking based on three receptor conformations to accommodate receptor flexibility. The model indicates that the dynamic character of the LBP allows accommodation and stable binding of structurally diverse ligands, and proper representation of the protein flexibility is critical for reasonable description of binding of the ligands. Our results provide a quantitative and mechanistic understanding of binding affinity and mode of ERα agonists and antagonists that may be applicable to other nuclear receptors.
authors.affiliation: U.S. Environmental Protection Agency, Gulf Ecology Division, Gulf Breeze, FL, United States of America.
authors.forename: Sehan
authors.identifier: http://orcid.org/0000-0003-4209-3519
authors.initials: S
authors.lastname: Lee
authors.affiliation: U.S. Environmental Protection Agency, Gulf Ecology Division, Gulf Breeze, FL, United States of America.
authors.forename: Mace G
authors.initials: MG
authors.lastname: Barron
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D052244:Endocrine Disruptors / Q000737:chemistry* / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results
chemical_list: D052244:Endocrine Disruptors; D047628:Estrogen Receptor alpha