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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

Characterization of the ligand binding site of β2AR variants.(A) Top-view of the β2AR represented as ribbons. The residues (113, 203, 289 and 312) that define the topology of the binding site are represented as licorice and the distances between them are indicated by lines. (B) Average distance between residues 289 and 203 for the Arg (red) and Gly (green) variants. (C) Average distance between residues 312 and 203 for the Arg (red) and Gly (green) variants. Docking of carazolol to (D) the 2RH1 structure, (E) Arg variant and (F) Gly variant. The crystal structure pose of carazolol is colored yellow, and the docked pose is colored purple.
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pcbi-1004006-g007: Characterization of the ligand binding site of β2AR variants.(A) Top-view of the β2AR represented as ribbons. The residues (113, 203, 289 and 312) that define the topology of the binding site are represented as licorice and the distances between them are indicated by lines. (B) Average distance between residues 289 and 203 for the Arg (red) and Gly (green) variants. (C) Average distance between residues 312 and 203 for the Arg (red) and Gly (green) variants. Docking of carazolol to (D) the 2RH1 structure, (E) Arg variant and (F) Gly variant. The crystal structure pose of carazolol is colored yellow, and the docked pose is colored purple.

Mentions: The ligand binding pocket of β2AR is comprised primarily of residues belonging to TM helices 3, 6 and 7. Residues 113, 203, 289 and 312 define the topology of the binding pocket of β2AR (Fig. 7 A). Out of these, residues 113, 289 and 312 (3.32, 6.51 and 7.39) have been observed to make consensus contacts with various ligands in the class A GPCRs [31]. We measured the distances between these residues across the six simulations of the two variants. We observe that the average distances of the residue 203 with 312 and 289 are about 0.5 nm larger for the Gly variant than that for the Arg variant (Fig. 7 B, C). It thus appears that the overall binding pocket of the Gly variant in all three simulations is marginally larger than that of the Arg variant.


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)

Characterization of the ligand binding site of β2AR variants.(A) Top-view of the β2AR represented as ribbons. The residues (113, 203, 289 and 312) that define the topology of the binding site are represented as licorice and the distances between them are indicated by lines. (B) Average distance between residues 289 and 203 for the Arg (red) and Gly (green) variants. (C) Average distance between residues 312 and 203 for the Arg (red) and Gly (green) variants. Docking of carazolol to (D) the 2RH1 structure, (E) Arg variant and (F) Gly variant. The crystal structure pose of carazolol is colored yellow, and the docked pose is colored purple.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1004006-g007: Characterization of the ligand binding site of β2AR variants.(A) Top-view of the β2AR represented as ribbons. The residues (113, 203, 289 and 312) that define the topology of the binding site are represented as licorice and the distances between them are indicated by lines. (B) Average distance between residues 289 and 203 for the Arg (red) and Gly (green) variants. (C) Average distance between residues 312 and 203 for the Arg (red) and Gly (green) variants. Docking of carazolol to (D) the 2RH1 structure, (E) Arg variant and (F) Gly variant. The crystal structure pose of carazolol is colored yellow, and the docked pose is colored purple.
Mentions: The ligand binding pocket of β2AR is comprised primarily of residues belonging to TM helices 3, 6 and 7. Residues 113, 203, 289 and 312 define the topology of the binding pocket of β2AR (Fig. 7 A). Out of these, residues 113, 289 and 312 (3.32, 6.51 and 7.39) have been observed to make consensus contacts with various ligands in the class A GPCRs [31]. We measured the distances between these residues across the six simulations of the two variants. We observe that the average distances of the residue 203 with 312 and 289 are about 0.5 nm larger for the Gly variant than that for the Arg variant (Fig. 7 B, C). It thus appears that the overall binding pocket of the Gly variant in all three simulations is marginally larger than that of the Arg variant.

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