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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

Secondary structure of the N-terminal region of the Arg and Gly variants of β2AR.Panels A, B and C represent simulation number 1, 2 and 3 of the Arg variant and panels D, E and F represent simulation number 1, 2 and 3 of the Gly variant, respectively. Turns are indicated by cyan color, 3–10 helices are indicated by blue, alpha helices are indicated by pink, isolated bridges are indicated by mustard and extended configuration is indicated by yellow color.
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pcbi-1004006-g004: Secondary structure of the N-terminal region of the Arg and Gly variants of β2AR.Panels A, B and C represent simulation number 1, 2 and 3 of the Arg variant and panels D, E and F represent simulation number 1, 2 and 3 of the Gly variant, respectively. Turns are indicated by cyan color, 3–10 helices are indicated by blue, alpha helices are indicated by pink, isolated bridges are indicated by mustard and extended configuration is indicated by yellow color.

Mentions: To quantify the structural differences at the N-terminal regions of the variants, the residue wise secondary structure was plotted over time (Fig. 4). In all three simulations of the Arg variant, after comprehensive sampling (400 ns onwards), a conformation comprising of two turns separated by nine to twelve residues is observed. The location of the turn varies between the simulations. The first turn is between residues 5–12 whereas the second is from 19–27. A turn that contains the 16th position arginine, in the initial model opens up in all three simulations. On the other hand, in the three simulations of the Gly variant the two turns are consistently present between residues 10 to 13 and 17 to 19. In two simulations of the Gly variant, an additional turn is formed towards the N-terminal. The backbone of arginine at the 16th position in all three simulations of the Arg variant displays a lack of secondary structure character, whilst the glycine displays mainly a turn conformation. It is known that due to its small size, uncharged nature and thus unusual conformational ability, glycine is found in turns and can easily accommodate a turn in its vicinity.


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)

Secondary structure of the N-terminal region of the Arg and Gly variants of β2AR.Panels A, B and C represent simulation number 1, 2 and 3 of the Arg variant and panels D, E and F represent simulation number 1, 2 and 3 of the Gly variant, respectively. Turns are indicated by cyan color, 3–10 helices are indicated by blue, alpha helices are indicated by pink, isolated bridges are indicated by mustard and extended configuration is indicated by yellow color.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1004006-g004: Secondary structure of the N-terminal region of the Arg and Gly variants of β2AR.Panels A, B and C represent simulation number 1, 2 and 3 of the Arg variant and panels D, E and F represent simulation number 1, 2 and 3 of the Gly variant, respectively. Turns are indicated by cyan color, 3–10 helices are indicated by blue, alpha helices are indicated by pink, isolated bridges are indicated by mustard and extended configuration is indicated by yellow color.
Mentions: To quantify the structural differences at the N-terminal regions of the variants, the residue wise secondary structure was plotted over time (Fig. 4). In all three simulations of the Arg variant, after comprehensive sampling (400 ns onwards), a conformation comprising of two turns separated by nine to twelve residues is observed. The location of the turn varies between the simulations. The first turn is between residues 5–12 whereas the second is from 19–27. A turn that contains the 16th position arginine, in the initial model opens up in all three simulations. On the other hand, in the three simulations of the Gly variant the two turns are consistently present between residues 10 to 13 and 17 to 19. In two simulations of the Gly variant, an additional turn is formed towards the N-terminal. The backbone of arginine at the 16th position in all three simulations of the Arg variant displays a lack of secondary structure character, whilst the glycine displays mainly a turn conformation. It is known that due to its small size, uncharged nature and thus unusual conformational ability, glycine is found in turns and can easily accommodate a turn in its vicinity.

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