Molecular Insights into the Dynamics of Pharmacogenetically Important N-Terminal Variants of the Human β2-Adrenergic Receptor

Ganesh Shahane, Chirag Parsania, Durba Sengupta and Manali Joshi

PLOS Computational Biology, 2014, vol. 10, issue 12, 1-10

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.Author Summary: The human β2-adrenergic receptor (β2AR) is an important member of the GPCR family and a mutation at the 16th position, Arg16Gly, is commonly found in the population. This variation in asthma patients is linked to differential (good/bad) response to the drug albuterol, an agonist of the β2AR. To date, the coordinates of the N-terminal residues harboring the 16th position mutation have not been resolved. In our study we sought to glean insights into the dynamics of the variants that could address the differential response to albuterol. We used knowledge from class A GPCRs to build the N-terminal region of β2AR variants in conjunction with the available structure of the inactive receptor. This was followed by atomistic simulations in triplicate totaling to a sampling of 6 µs. We observe that the N-terminal region of the Arg variant is more dynamic than the Gly variant. Amongst the various differences between the variants, we observe long-range effects at the binding site leading to preferential docking of albuterol to the Gly variant. Our work is a first step to unravel the molecular mechanism linking the Arg16Gly variation to the differential response to albuterol in asthma patients.

Date: 2014
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1004006

DOI: 10.1371/journal.pcbi.1004006

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