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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

Contact maps of Arg and Gly variants of β2AR.Contacts between the N-terminal region of (A) Arg and (B) Gly variants and the rest of the receptor were computed from the average distance over simulation time. Average distances that were less than or equal to 1 nm were plotted. A color bar is indicated in which white indicates no-contacts and black indicates a close contact.
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pcbi-1004006-g005: Contact maps of Arg and Gly variants of β2AR.Contacts between the N-terminal region of (A) Arg and (B) Gly variants and the rest of the receptor were computed from the average distance over simulation time. Average distances that were less than or equal to 1 nm were plotted. A color bar is indicated in which white indicates no-contacts and black indicates a close contact.

Mentions: Further, side chain contacts of the N-terminal region with the receptor were calculated (Fig. 5). In addition, the contacts within 0.3 nm for at least 30% of the simulation time were calculated (S2 Table). A striking difference is seen in the number of contacts of the first fourteen residues of the variants. The Arg variant has very few contacts with the remaining receptor, while the residues of the Gly variant have several contacts as a result of the differential placement of the N-terminal region. Interestingly, the 16th position arginine has several contacts with the receptor while the glycine at the 16th position in the Gly variant has none. Further, residues 21 to 26 in the Gly variant interact with Glu 306 anchoring the N-terminal region to the 7th helix. The residues 21 to 26 in the Arg variant on the other hand are closer to TM helix 2.


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)

Contact maps of Arg and Gly variants of β2AR.Contacts between the N-terminal region of (A) Arg and (B) Gly variants and the rest of the receptor were computed from the average distance over simulation time. Average distances that were less than or equal to 1 nm were plotted. A color bar is indicated in which white indicates no-contacts and black indicates a close contact.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1004006-g005: Contact maps of Arg and Gly variants of β2AR.Contacts between the N-terminal region of (A) Arg and (B) Gly variants and the rest of the receptor were computed from the average distance over simulation time. Average distances that were less than or equal to 1 nm were plotted. A color bar is indicated in which white indicates no-contacts and black indicates a close contact.
Mentions: Further, side chain contacts of the N-terminal region with the receptor were calculated (Fig. 5). In addition, the contacts within 0.3 nm for at least 30% of the simulation time were calculated (S2 Table). A striking difference is seen in the number of contacts of the first fourteen residues of the variants. The Arg variant has very few contacts with the remaining receptor, while the residues of the Gly variant have several contacts as a result of the differential placement of the N-terminal region. Interestingly, the 16th position arginine has several contacts with the receptor while the glycine at the 16th position in the Gly variant has none. Further, residues 21 to 26 in the Gly variant interact with Glu 306 anchoring the N-terminal region to the 7th helix. The residues 21 to 26 in the Arg variant on the other hand are closer to TM helix 2.

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