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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

Five interconnected residues in the carazolol-bound structure of the β2AR (PDB ID: 2RH1). Panel a: a three-dimensional atomic model of the five residues, with dotted double headed arrows indicating the shortest physical distance between Asp 113 and its neighboring residues and cyan lines indicating residues that establish contacts according to the CSU analysis; the residues are shown in balls and sticks format, with carbon atoms colored in gray, oxygen atoms in red, nitrogen atoms in blue and hydrogen atoms in white. Panel b: a graph representation in which the five residues are shown as nodes, with edges connecting the residues that establish contacts according to the CSU analysis. Panel c: physical distance between the closest atoms of Asp 113 and each other shown residue (represented as dotted double headed arrows in panel a) and connectivity distance between Asp 113 and each of the other residues shown, as inferred from the graph. All connectivity distances are calculated along the shortest paths. For instance, the green edge in panel a shows the shortest path from node 1 to node 3, while the red edges show an alternative longer path. Panel d: mathematical formula for the calculation of closeness-centrality (C) of node x, where n = number of nodes in the graph; d(x, y) = geodesic connectivity distance, i.e. the shortest path, between node x and node y; U = the set of all nodes. If the four shown residues were the only four nodes in the graph representation of the 2RH1 structure, their closeness centrality would be 0.57 for Val 86, 0.57 for Asp 113, 0.44 for Phe 289, 0.67 for Asn 312 and 0.80 for Tyr 316.
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Fig1: Five interconnected residues in the carazolol-bound structure of the β2AR (PDB ID: 2RH1). Panel a: a three-dimensional atomic model of the five residues, with dotted double headed arrows indicating the shortest physical distance between Asp 113 and its neighboring residues and cyan lines indicating residues that establish contacts according to the CSU analysis; the residues are shown in balls and sticks format, with carbon atoms colored in gray, oxygen atoms in red, nitrogen atoms in blue and hydrogen atoms in white. Panel b: a graph representation in which the five residues are shown as nodes, with edges connecting the residues that establish contacts according to the CSU analysis. Panel c: physical distance between the closest atoms of Asp 113 and each other shown residue (represented as dotted double headed arrows in panel a) and connectivity distance between Asp 113 and each of the other residues shown, as inferred from the graph. All connectivity distances are calculated along the shortest paths. For instance, the green edge in panel a shows the shortest path from node 1 to node 3, while the red edges show an alternative longer path. Panel d: mathematical formula for the calculation of closeness-centrality (C) of node x, where n = number of nodes in the graph; d(x, y) = geodesic connectivity distance, i.e. the shortest path, between node x and node y; U = the set of all nodes. If the four shown residues were the only four nodes in the graph representation of the 2RH1 structure, their closeness centrality would be 0.57 for Val 86, 0.57 for Asp 113, 0.44 for Phe 289, 0.67 for Asn 312 and 0.80 for Tyr 316.

Mentions: Here, we analyze the structure of the β2 AR through graph theory, a technique that has recently emerged as a tool applicable to the study of the global structural aspects of proteins (Di Paola et al. 2013; 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; del Sol et al. 2006b). In this approach, protein structures are described as a graph consisting of a number of nodes, i.e. the amino acid residues that make up the protein, connected by edges, i.e. the non-covalent interactions occurring between the residues (Figure 1a-c). Just like members of a social network, each residue of a protein has a certain number of first-degree connections, i.e. residues in direct contact, a certain number of second-degree connections, i.e. residues that are not in direct contact but share a common residue with which they are both in contact. Ultimately, each residue of the receptor is connected with every other residue of the receptor, although with different degrees of connectivity. This network of interconnected residues can be studied through the same analysis tools employed to analyze social networks of interconnected people, revealing patterns of connectivity, influential members, and dynamic behavior. Notably, in a seminal study published in 2006, Nussinov and coworkers applied graph theory to the study of rhodopsin, when this was still the only GPCR with an experimentally elucidated three-dimensional structure (del Sol et al. 2006b). In particular, the authors represented the structure of rhodopsin as a network of interacting residues and, removing residues from the network, identified those that play key roles in maintaining long-range interactions between distal regions of the receptor.Figure 1


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)

Five interconnected residues in the carazolol-bound structure of the β2AR (PDB ID: 2RH1). Panel a: a three-dimensional atomic model of the five residues, with dotted double headed arrows indicating the shortest physical distance between Asp 113 and its neighboring residues and cyan lines indicating residues that establish contacts according to the CSU analysis; the residues are shown in balls and sticks format, with carbon atoms colored in gray, oxygen atoms in red, nitrogen atoms in blue and hydrogen atoms in white. Panel b: a graph representation in which the five residues are shown as nodes, with edges connecting the residues that establish contacts according to the CSU analysis. Panel c: physical distance between the closest atoms of Asp 113 and each other shown residue (represented as dotted double headed arrows in panel a) and connectivity distance between Asp 113 and each of the other residues shown, as inferred from the graph. All connectivity distances are calculated along the shortest paths. For instance, the green edge in panel a shows the shortest path from node 1 to node 3, while the red edges show an alternative longer path. Panel d: mathematical formula for the calculation of closeness-centrality (C) of node x, where n = number of nodes in the graph; d(x, y) = geodesic connectivity distance, i.e. the shortest path, between node x and node y; U = the set of all nodes. If the four shown residues were the only four nodes in the graph representation of the 2RH1 structure, their closeness centrality would be 0.57 for Val 86, 0.57 for Asp 113, 0.44 for Phe 289, 0.67 for Asn 312 and 0.80 for Tyr 316.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4230308&req=5

Fig1: Five interconnected residues in the carazolol-bound structure of the β2AR (PDB ID: 2RH1). Panel a: a three-dimensional atomic model of the five residues, with dotted double headed arrows indicating the shortest physical distance between Asp 113 and its neighboring residues and cyan lines indicating residues that establish contacts according to the CSU analysis; the residues are shown in balls and sticks format, with carbon atoms colored in gray, oxygen atoms in red, nitrogen atoms in blue and hydrogen atoms in white. Panel b: a graph representation in which the five residues are shown as nodes, with edges connecting the residues that establish contacts according to the CSU analysis. Panel c: physical distance between the closest atoms of Asp 113 and each other shown residue (represented as dotted double headed arrows in panel a) and connectivity distance between Asp 113 and each of the other residues shown, as inferred from the graph. All connectivity distances are calculated along the shortest paths. For instance, the green edge in panel a shows the shortest path from node 1 to node 3, while the red edges show an alternative longer path. Panel d: mathematical formula for the calculation of closeness-centrality (C) of node x, where n = number of nodes in the graph; d(x, y) = geodesic connectivity distance, i.e. the shortest path, between node x and node y; U = the set of all nodes. If the four shown residues were the only four nodes in the graph representation of the 2RH1 structure, their closeness centrality would be 0.57 for Val 86, 0.57 for Asp 113, 0.44 for Phe 289, 0.67 for Asn 312 and 0.80 for Tyr 316.
Mentions: Here, we analyze the structure of the β2 AR through graph theory, a technique that has recently emerged as a tool applicable to the study of the global structural aspects of proteins (Di Paola et al. 2013; 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; del Sol et al. 2006b). In this approach, protein structures are described as a graph consisting of a number of nodes, i.e. the amino acid residues that make up the protein, connected by edges, i.e. the non-covalent interactions occurring between the residues (Figure 1a-c). Just like members of a social network, each residue of a protein has a certain number of first-degree connections, i.e. residues in direct contact, a certain number of second-degree connections, i.e. residues that are not in direct contact but share a common residue with which they are both in contact. Ultimately, each residue of the receptor is connected with every other residue of the receptor, although with different degrees of connectivity. This network of interconnected residues can be studied through the same analysis tools employed to analyze social networks of interconnected people, revealing patterns of connectivity, influential members, and dynamic behavior. Notably, in a seminal study published in 2006, Nussinov and coworkers applied graph theory to the study of rhodopsin, when this was still the only GPCR with an experimentally elucidated three-dimensional structure (del Sol et al. 2006b). In particular, the authors represented the structure of rhodopsin as a network of interacting residues and, removing residues from the network, identified those that play key roles in maintaining long-range interactions between distal regions of the receptor.Figure 1

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