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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

Three alternative views of two of the experimentally solved structures of the β2AR, one solved in the inactive state (2RH1) and one in an activated state (3P0G). A key residue in the activation of the receptor, namely Phe 2826.44, is shown with its non-hydrogen atoms represented as spheres and colored in red for the 2RH1 structure and green for the 3P0G structure. The backbone of the receptor is schematically portrayed as a ribbon for the 2RH1 structure and as a tube for the 3P0G structure and is colored with a continuous spectrum ranging from red at the N-terminus to purple at the C-terminus, with TM1 in red/orange, TM2 in orange, TM3 in yellow, TM4 in yellow/green, TM5 in green, TM6 in blue and TM7 in purple. In the views provided in panels b and c the receptor is rotated clockwise (when observed from the extracellular space) of 60° and 340° degrees around its main axis with the respect to the view provided in panel a. The bow tie shape of the receptor is particularly evident from panel b.
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Fig2: Three alternative views of two of the experimentally solved structures of the β2AR, one solved in the inactive state (2RH1) and one in an activated state (3P0G). A key residue in the activation of the receptor, namely Phe 2826.44, is shown with its non-hydrogen atoms represented as spheres and colored in red for the 2RH1 structure and green for the 3P0G structure. The backbone of the receptor is schematically portrayed as a ribbon for the 2RH1 structure and as a tube for the 3P0G structure and is colored with a continuous spectrum ranging from red at the N-terminus to purple at the C-terminus, with TM1 in red/orange, TM2 in orange, TM3 in yellow, TM4 in yellow/green, TM5 in green, TM6 in blue and TM7 in purple. In the views provided in panels b and c the receptor is rotated clockwise (when observed from the extracellular space) of 60° and 340° degrees around its main axis with the respect to the view provided in panel a. The bow tie shape of the receptor is particularly evident from panel b.

Mentions: In social networks, highly connected individuals tend to have a high influence on society (Wasserman and Faust 1994). Equally, residues endowed with high closeness-centrality have been found to be critical for the function of enzymes and to be generally located in the catalytic sites (Amitai et al. 2004; Thibert et al. 2005; Tang et al. 2008; Slama et al. 2008; Pathak et al. 2013; del Sol et al. 2006a; Chea and Livesay 2007). Notably, the same functional importance has been detected for nucleotide residues in ribosomes (David-Eden and Mandel-Gutfreund 2008). A further study from Nussinov and coworkers revealed that, for non-enzyme proteins, although residues endowed with high closeness-centrality are generally important for fold and function, they are often not located within their binding sites (del Sol et al. 2006a). The results of our study are completely in line with these findings. In particular, they revealed that the β2 AR residues endowed with the highest closeness-centrality are located in the core of the receptor. As a consequence, the receptor can be likened to a bow tie (Figure 2), with a rather tight knot of highly central and closely interacting 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.Figure 2


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)

Three alternative views of two of the experimentally solved structures of the β2AR, one solved in the inactive state (2RH1) and one in an activated state (3P0G). A key residue in the activation of the receptor, namely Phe 2826.44, is shown with its non-hydrogen atoms represented as spheres and colored in red for the 2RH1 structure and green for the 3P0G structure. The backbone of the receptor is schematically portrayed as a ribbon for the 2RH1 structure and as a tube for the 3P0G structure and is colored with a continuous spectrum ranging from red at the N-terminus to purple at the C-terminus, with TM1 in red/orange, TM2 in orange, TM3 in yellow, TM4 in yellow/green, TM5 in green, TM6 in blue and TM7 in purple. In the views provided in panels b and c the receptor is rotated clockwise (when observed from the extracellular space) of 60° and 340° degrees around its main axis with the respect to the view provided in panel a. The bow tie shape of the receptor is particularly evident from panel b.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: Three alternative views of two of the experimentally solved structures of the β2AR, one solved in the inactive state (2RH1) and one in an activated state (3P0G). A key residue in the activation of the receptor, namely Phe 2826.44, is shown with its non-hydrogen atoms represented as spheres and colored in red for the 2RH1 structure and green for the 3P0G structure. The backbone of the receptor is schematically portrayed as a ribbon for the 2RH1 structure and as a tube for the 3P0G structure and is colored with a continuous spectrum ranging from red at the N-terminus to purple at the C-terminus, with TM1 in red/orange, TM2 in orange, TM3 in yellow, TM4 in yellow/green, TM5 in green, TM6 in blue and TM7 in purple. In the views provided in panels b and c the receptor is rotated clockwise (when observed from the extracellular space) of 60° and 340° degrees around its main axis with the respect to the view provided in panel a. The bow tie shape of the receptor is particularly evident from panel b.
Mentions: In social networks, highly connected individuals tend to have a high influence on society (Wasserman and Faust 1994). Equally, residues endowed with high closeness-centrality have been found to be critical for the function of enzymes and to be generally located in the catalytic sites (Amitai et al. 2004; Thibert et al. 2005; Tang et al. 2008; Slama et al. 2008; Pathak et al. 2013; del Sol et al. 2006a; Chea and Livesay 2007). Notably, the same functional importance has been detected for nucleotide residues in ribosomes (David-Eden and Mandel-Gutfreund 2008). A further study from Nussinov and coworkers revealed that, for non-enzyme proteins, although residues endowed with high closeness-centrality are generally important for fold and function, they are often not located within their binding sites (del Sol et al. 2006a). The results of our study are completely in line with these findings. In particular, they revealed that the β2 AR residues endowed with the highest closeness-centrality are located in the core of the receptor. As a consequence, the receptor can be likened to a bow tie (Figure 2), with a rather tight knot of highly central and closely interacting 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.Figure 2

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