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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

Vestibules of ligand entry in β2AR variants.Grids representing vestibule openings for (A) vestibule1 and (B) vestibule 2 of β2AR are shown in yellow. Residues defining the vestibules are shown in surface representation while the rest of the receptor is rendered as ribbons and colored blue. Panel C and D represent volumes (in Å3) of the non-occluded grid of vestibule 1 for the Arg and Gly variants, respectively. Panel E and F represent volumes (in Å3) of the non-occluded grid of vestibule 2 for the Arg and Gly variants, respectively. For each plot, the blue line indicates the first simulation, the red indicates the second and the green line indicates the third simulation.
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pcbi-1004006-g006: Vestibules of ligand entry in β2AR variants.Grids representing vestibule openings for (A) vestibule1 and (B) vestibule 2 of β2AR are shown in yellow. Residues defining the vestibules are shown in surface representation while the rest of the receptor is rendered as ribbons and colored blue. Panel C and D represent volumes (in Å3) of the non-occluded grid of vestibule 1 for the Arg and Gly variants, respectively. Panel E and F represent volumes (in Å3) of the non-occluded grid of vestibule 2 for the Arg and Gly variants, respectively. For each plot, the blue line indicates the first simulation, the red indicates the second and the green line indicates the third simulation.

Mentions: The average volumes of the non-occluded grid points defining the vestibules was calculated and plotted against time (Fig. 6). Substantial fluctuations are observed in the volumes of the vestibule openings due to mobility of the side chains of the residues that line them. The plots indicate that the Gly variants on an average tend to have a more open vestibule 1 than their Arg counterparts. In the first 250 ns of the third simulation of the Gly variant, vestibule 1 opens up more due to lateral movement of the N-terminal region towards TM helix 6 and 7. The increased size of the vestibule is comparable to that observed in the crystal structure (2RH1). In the simulations of the Arg variants, the arginine residue at the 16th position interacts with residues lining vestibule 1 and in two out of three simulations partially blocks the vestibule with its bulky side chain. On the other hand, in the Gly variant the 16th position glycine is rarely seen to interact with the residues lining the vestibule, although residues 6 to 8 of the N-terminal region interact directly with these residues.


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)

Vestibules of ligand entry in β2AR variants.Grids representing vestibule openings for (A) vestibule1 and (B) vestibule 2 of β2AR are shown in yellow. Residues defining the vestibules are shown in surface representation while the rest of the receptor is rendered as ribbons and colored blue. Panel C and D represent volumes (in Å3) of the non-occluded grid of vestibule 1 for the Arg and Gly variants, respectively. Panel E and F represent volumes (in Å3) of the non-occluded grid of vestibule 2 for the Arg and Gly variants, respectively. For each plot, the blue line indicates the first simulation, the red indicates the second and the green line indicates the third simulation.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1004006-g006: Vestibules of ligand entry in β2AR variants.Grids representing vestibule openings for (A) vestibule1 and (B) vestibule 2 of β2AR are shown in yellow. Residues defining the vestibules are shown in surface representation while the rest of the receptor is rendered as ribbons and colored blue. Panel C and D represent volumes (in Å3) of the non-occluded grid of vestibule 1 for the Arg and Gly variants, respectively. Panel E and F represent volumes (in Å3) of the non-occluded grid of vestibule 2 for the Arg and Gly variants, respectively. For each plot, the blue line indicates the first simulation, the red indicates the second and the green line indicates the third simulation.
Mentions: The average volumes of the non-occluded grid points defining the vestibules was calculated and plotted against time (Fig. 6). Substantial fluctuations are observed in the volumes of the vestibule openings due to mobility of the side chains of the residues that line them. The plots indicate that the Gly variants on an average tend to have a more open vestibule 1 than their Arg counterparts. In the first 250 ns of the third simulation of the Gly variant, vestibule 1 opens up more due to lateral movement of the N-terminal region towards TM helix 6 and 7. The increased size of the vestibule is comparable to that observed in the crystal structure (2RH1). In the simulations of the Arg variants, the arginine residue at the 16th position interacts with residues lining vestibule 1 and in two out of three simulations partially blocks the vestibule with its bulky side chain. On the other hand, in the Gly variant the 16th position glycine is rarely seen to interact with the residues lining the vestibule, although residues 6 to 8 of the N-terminal region interact directly with these residues.

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