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Graph analysis of β2 adrenergic receptor structures: a "social network" of GPCR residues.

Sheftel S, Muratore KE, Black M, Costanzi S - In Silico Pharmacol (2013)

Bottom Line: At the cytosolic end of TM6, the centrality detected for the active structure is markedly lower than that detected for the corresponding residues in the inactive structures.Strikingly, there is little overlap between the residues that acquire centrality in the presence of the ligand in the blocker-bound structures and the agonist-bound structures.Moreover, they underscore how interaction network is by the conformational rearrangements concomitant with the activation of the receptor and by the presence of agonists or blockers.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, American University, 4400 Massachusetts Ave, Northwest, Washington, DC 20016 USA.

ABSTRACT

Purpose: G protein-coupled receptors (GPCRs) are a superfamily of membrane proteins of vast pharmaceutical interest. Here, we describe a graph theory-based analysis of the structure of the β2 adrenergic receptor (β2 AR), a prototypical GPCR. In particular, we illustrate the network of direct and indirect interactions that link each amino acid residue to any other residue of the receptor.

Methods: Networks of interconnected amino acid residues in proteins are analogous to social networks of interconnected people. Hence, they can be studied through the same analysis tools typically employed to analyze social networks - or networks in general - to reveal patterns of connectivity, influential members, and dynamicity. We focused on the analysis of closeness-centrality, which is a measure of the overall connectivity distance of the member of a network to all other members.

Results: The residues endowed with the highest closeness-centrality are located in the middle of the seven transmembrane domains (TMs). In particular, they are mostly located in the middle of TM2, TM3, TM6 or TM7, while fewer of them are located in the middle of TM1, TM4 or TM5. At the cytosolic end of TM6, the centrality detected for the active structure is markedly lower than that detected for the corresponding residues in the inactive structures. Moreover, several residues acquire centrality when the structures are analyzed in the presence of ligands. Strikingly, there is little overlap between the residues that acquire centrality in the presence of the ligand in the blocker-bound structures and the agonist-bound structures.

Conclusions: Our results reflect the fact that the receptor resembles a bow tie, with a rather tight knot of closely interconnected residues and two ends that fan out in two opposite directions: one toward the extracellular space, which hosts the ligand binding cavity, and one toward the cytosol, which hosts the G protein binding cavity. Moreover, they underscore how interaction network is by the conformational rearrangements concomitant with the activation of the receptor and by the presence of agonists or blockers.

No MeSH data available.


Related in: MedlinePlus

Molecular structures of the seven ligands crystallized with the β2AR in the published structures. Compounds 1–5 are blockers, while compound 6–7 are agonists. Of note, compound 6 is covalently bound to a Cys residue artificially introduced in place of His 932.64 in TM2.
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Fig6: Molecular structures of the seven ligands crystallized with the β2AR in the published structures. Compounds 1–5 are blockers, while compound 6–7 are agonists. Of note, compound 6 is covalently bound to a Cys residue artificially introduced in place of His 932.64 in TM2.

Mentions: A total of 12 crystal structures have been solved for the β2 AR, in complex with 7 different ligands (Figure 6). Our study is based on the analysis of 7 of these structures, each of which is representative of the complex between the receptor and one of the 7 different ligands with which it has been co-crystallized. In order to make the comparison among different structures possible, we analyzed only the portion of the receptor solved in all the studied structures, expunging the residues that were solved only in a subset of the structure – the resulting amino acid sequence of the analyzed structures is shown in Additional file 1: Figure S2. Specifically, the analyzed sequence comprised the entire segment (including all the intervening loops) from the beginning of TM1 to the end of TM4 and the entire segment (including all the intervening loops) from the beginning of TM5 to the end of helix 8 (H8), which is an amphipathic cytosolic helix that immediately follows TM7 (Additional file 1: Figure S2).Figure 6


Graph analysis of β2 adrenergic receptor structures: a "social network" of GPCR residues.

Sheftel S, Muratore KE, Black M, Costanzi S - In Silico Pharmacol (2013)

Molecular structures of the seven ligands crystallized with the β2AR in the published structures. Compounds 1–5 are blockers, while compound 6–7 are agonists. Of note, compound 6 is covalently bound to a Cys residue artificially introduced in place of His 932.64 in TM2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230308&req=5

Fig6: Molecular structures of the seven ligands crystallized with the β2AR in the published structures. Compounds 1–5 are blockers, while compound 6–7 are agonists. Of note, compound 6 is covalently bound to a Cys residue artificially introduced in place of His 932.64 in TM2.
Mentions: A total of 12 crystal structures have been solved for the β2 AR, in complex with 7 different ligands (Figure 6). Our study is based on the analysis of 7 of these structures, each of which is representative of the complex between the receptor and one of the 7 different ligands with which it has been co-crystallized. In order to make the comparison among different structures possible, we analyzed only the portion of the receptor solved in all the studied structures, expunging the residues that were solved only in a subset of the structure – the resulting amino acid sequence of the analyzed structures is shown in Additional file 1: Figure S2. Specifically, the analyzed sequence comprised the entire segment (including all the intervening loops) from the beginning of TM1 to the end of TM4 and the entire segment (including all the intervening loops) from the beginning of TM5 to the end of helix 8 (H8), which is an amphipathic cytosolic helix that immediately follows TM7 (Additional file 1: Figure S2).Figure 6

Bottom Line: At the cytosolic end of TM6, the centrality detected for the active structure is markedly lower than that detected for the corresponding residues in the inactive structures.Strikingly, there is little overlap between the residues that acquire centrality in the presence of the ligand in the blocker-bound structures and the agonist-bound structures.Moreover, they underscore how interaction network is by the conformational rearrangements concomitant with the activation of the receptor and by the presence of agonists or blockers.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, American University, 4400 Massachusetts Ave, Northwest, Washington, DC 20016 USA.

ABSTRACT

Purpose: G protein-coupled receptors (GPCRs) are a superfamily of membrane proteins of vast pharmaceutical interest. Here, we describe a graph theory-based analysis of the structure of the β2 adrenergic receptor (β2 AR), a prototypical GPCR. In particular, we illustrate the network of direct and indirect interactions that link each amino acid residue to any other residue of the receptor.

Methods: Networks of interconnected amino acid residues in proteins are analogous to social networks of interconnected people. Hence, they can be studied through the same analysis tools typically employed to analyze social networks - or networks in general - to reveal patterns of connectivity, influential members, and dynamicity. We focused on the analysis of closeness-centrality, which is a measure of the overall connectivity distance of the member of a network to all other members.

Results: The residues endowed with the highest closeness-centrality are located in the middle of the seven transmembrane domains (TMs). In particular, they are mostly located in the middle of TM2, TM3, TM6 or TM7, while fewer of them are located in the middle of TM1, TM4 or TM5. At the cytosolic end of TM6, the centrality detected for the active structure is markedly lower than that detected for the corresponding residues in the inactive structures. Moreover, several residues acquire centrality when the structures are analyzed in the presence of ligands. Strikingly, there is little overlap between the residues that acquire centrality in the presence of the ligand in the blocker-bound structures and the agonist-bound structures.

Conclusions: Our results reflect the fact that the receptor resembles a bow tie, with a rather tight knot of closely interconnected residues and two ends that fan out in two opposite directions: one toward the extracellular space, which hosts the ligand binding cavity, and one toward the cytosol, which hosts the G protein binding cavity. Moreover, they underscore how interaction network is by the conformational rearrangements concomitant with the activation of the receptor and by the presence of agonists or blockers.

No MeSH data available.


Related in: MedlinePlus