title: Molecular insights into the dynamics of pharmacogenetically important N-terminal variants of the human β2-adrenergic receptor.
abstract: The human β2-adrenergic receptor (β2AR), a member of the G-protein coupled receptor (GPCR) family, is expressed in bronchial smooth muscle cells. Upon activation by agonists, β2AR causes bronchodilation and relief in asthma patients. The N-terminal polymorphism of β2AR at the 16th position, Arg16Gly, has warranted a lot of attention since it is linked to variations in response to albuterol (agonist) treatment. Although the β2AR is one of the well-studied GPCRs, the N-terminus which harbors this mutation, is absent in all available experimental structures. The goal of this work was to study the molecular level differences between the N-terminal variants using structural modeling and atomistic molecular dynamics simulations. Our simulations reveal that the N-terminal region of the Arg variant shows greater dynamics than the Gly variant, leading to differential placement. Further, the position and dynamics of the N-terminal region, further, affects the ligand binding-site accessibility. Interestingly, long-range effects are also seen at the ligand binding site, which is marginally larger in the Gly as compared to the Arg variant resulting in the preferential docking of albuterol to the Gly variant. This study thus reveals key differences between the variants providing a molecular framework towards understanding the variable drug response in asthma patients.
authors.affiliation: CSIR-National Chemical Laboratory, Pune, India.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Shahane
authors.affiliation: Bioinformatics Center, University of Pune, Pune, India.
authors.forename: Chirag
authors.initials: C
authors.lastname: Parsania
authors.affiliation: CSIR-National Chemical Laboratory, Pune, India.
authors.forename: Durba
authors.initials: D
authors.lastname: Sengupta
authors.affiliation: Bioinformatics Center, University of Pune, Pune, India.
authors.forename: Manali
authors.initials: M
authors.lastname: Joshi
mesh_terms: D000420:Albuterol / Q000737:chemistry / Q000378:metabolism; D001249:Asthma / Q000235:genetics; D001665:Binding Sites / Q000235:genetics*; D006801:Humans; D056004:Molecular Dynamics Simulation; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
chemical_list: D018343:Receptors, Adrenergic, beta-2; D000420:Albuterol