Differential Dynamics Underlying the Gln27Glu Population Variant of the β2-Adrenergic Receptor
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The β2-adrenergic receptor (β2AR) is a membrane-bound G-protein-coupled receptor and an important drug target for asthma. Clinical studies report that the population variant Gln27Glu is associated with a differential response to common asthma drugs, such as albuterol, isoproterenol and terbutaline. Interestingly, the 27th amino acid is positioned on the N-terminal region that is the most flexible and consequently the least studied part of the receptor. In this study, we probe the molecular origin of the differential drug binding by performing structural modeling and simulations of the wild-type (Gln) and variant (Glu) receptors followed by ensemble docking with the ligands, albuterol, isoproterenol and terbutaline. In line with clinical studies, the ligands were observed to interact preferentially with the Glu variant. Our results indicate that the Glu residue at the 27th position perturbs the network of electrostatic interactions that connects the N-terminal region to the binding site in the wild-type receptor. As a result, the Glu variant is observed to bind better to the three ligands tested in this study. Our study provides a structural basis to explain the variable drug response associated with the 27th position polymorphism in the β2AR and is a starting step to identify genotype-specific therapeutics.
Keywordsβ2-Adrenergic receptor SNP Molecular dynamics G-protein-coupled receptor GPCR Pharmacogenetics
Sumedha Bhosale acknowledges studentship received from Department of Biotechnology (DBT), India. Siddhanta V. Nikte thanks the DBT for Junior Research Fellowship. Manali Joshi thanks the Bioinformatics Centre for infrastructure support. Durba Sengupta gratefully acknowledges the project (EMR/2016/002294) from Dept. Science Technology, India.
This study was funded by EMR/2016/002294 from Dept. Science Technology, India.
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflict of interest.
This article does not contain any studies with human participants or animals performed by any of the authors.
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