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Molecular insights into the dynamics of pharmacogenetically important N-terminal variants of the human β2-adrenergic receptor.

Shahane G, Parsania C, Sengupta D, Joshi M - PLoS Comput. Biol. (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: CSIR-National Chemical Laboratory, Pune, India.

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.

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Related in: MedlinePlus

Top-view snapshots of the Arg and Gly variants of β2AR during the course of the simulation.The snapshots are shown at time intervals of 250 ns. Panel A, B and C represent simulation number 1, 2 and 3 of the Arg variant and panel D, E and F represent simulation number 1, 2 and 3 of the Gly variant, respectively. The protein is rendered as ribbons and the N-terminal residues are colored black.
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pcbi-1004006-g003: Top-view snapshots of the Arg and Gly variants of β2AR during the course of the simulation.The snapshots are shown at time intervals of 250 ns. Panel A, B and C represent simulation number 1, 2 and 3 of the Arg variant and panel D, E and F represent simulation number 1, 2 and 3 of the Gly variant, respectively. The protein is rendered as ribbons and the N-terminal residues are colored black.

Mentions: To visualize the differences in the N-terminal region between the variants, representative snapshots of the protein from the trajectories were analyzed (Fig. 3). In all the three simulations of the Gly variants the N-terminal region is found to stay on top of the TM helices. In contrast, the Arg variants show larger dynamics and tend to open up partially.


Molecular insights into the dynamics of pharmacogenetically important N-terminal variants of the human β2-adrenergic receptor.

Shahane G, Parsania C, Sengupta D, Joshi M - PLoS Comput. Biol. (2014)

Top-view snapshots of the Arg and Gly variants of β2AR during the course of the simulation.The snapshots are shown at time intervals of 250 ns. Panel A, B and C represent simulation number 1, 2 and 3 of the Arg variant and panel D, E and F represent simulation number 1, 2 and 3 of the Gly variant, respectively. The protein is rendered as ribbons and the N-terminal residues are colored black.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4263363&req=5

pcbi-1004006-g003: Top-view snapshots of the Arg and Gly variants of β2AR during the course of the simulation.The snapshots are shown at time intervals of 250 ns. Panel A, B and C represent simulation number 1, 2 and 3 of the Arg variant and panel D, E and F represent simulation number 1, 2 and 3 of the Gly variant, respectively. The protein is rendered as ribbons and the N-terminal residues are colored black.
Mentions: To visualize the differences in the N-terminal region between the variants, representative snapshots of the protein from the trajectories were analyzed (Fig. 3). In all the three simulations of the Gly variants the N-terminal region is found to stay on top of the TM helices. In contrast, the Arg variants show larger dynamics and tend to open up partially.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: CSIR-National Chemical Laboratory, Pune, India.

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.

Show MeSH
Related in: MedlinePlus