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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

Closeness-centrality of all residues in the seven analyzed structures. The seven peaks of high closeness-centrality identify residues located in the middle of each of the seven transmembrane domains of the receptor. In particular, most of the residues characterized by high closeness-centrality are located in the middle of TM2, TM3, TM6 and TM7.
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Fig7: Closeness-centrality of all residues in the seven analyzed structures. The seven peaks of high closeness-centrality identify residues located in the middle of each of the seven transmembrane domains of the receptor. In particular, most of the residues characterized by high closeness-centrality are located in the middle of TM2, TM3, TM6 and TM7.

Mentions: Our first level of analysis focused on the identification of the residues with the highest centrality in the seven studied structures. As Figure 7 shows, plotting the centrality value versus the residue numbers reveals the presence of seven peaks corresponding to regions with highly connected residues. Mapping on the crystal structures the most highly connected residues – more specifically the residues for which the centrality value was equal or higher than a cutoff value set to the average plus the standard deviation across all residues (centrality ≥ 0.255) – reveals that each of these seven regions is located in the middle of one of the seven transmembrane domains of the receptor (Figure 8). The centrality values for the mapped residues are numerically reported in Additional file 1: Table S1, which reveals that most of the highly connected residues are located in the middle of TM2, TM3, TM6 or TM7, while a substantially narrower number of highly connected residues are located in the middle of TM1, TM4 or TM5. There are no substantial differences in the pool of residues with the highest centrality in the seven analyzed structures. The only notable exception concerns the activated structure (3P0G), for which residues located toward the cytosolic end of the middle portion of TM6 show a lower centrality when compared to their counterparts in the inactive structures.Figure 7


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)

Closeness-centrality of all residues in the seven analyzed structures. The seven peaks of high closeness-centrality identify residues located in the middle of each of the seven transmembrane domains of the receptor. In particular, most of the residues characterized by high closeness-centrality are located in the middle of TM2, TM3, TM6 and TM7.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig7: Closeness-centrality of all residues in the seven analyzed structures. The seven peaks of high closeness-centrality identify residues located in the middle of each of the seven transmembrane domains of the receptor. In particular, most of the residues characterized by high closeness-centrality are located in the middle of TM2, TM3, TM6 and TM7.
Mentions: Our first level of analysis focused on the identification of the residues with the highest centrality in the seven studied structures. As Figure 7 shows, plotting the centrality value versus the residue numbers reveals the presence of seven peaks corresponding to regions with highly connected residues. Mapping on the crystal structures the most highly connected residues – more specifically the residues for which the centrality value was equal or higher than a cutoff value set to the average plus the standard deviation across all residues (centrality ≥ 0.255) – reveals that each of these seven regions is located in the middle of one of the seven transmembrane domains of the receptor (Figure 8). The centrality values for the mapped residues are numerically reported in Additional file 1: Table S1, which reveals that most of the highly connected residues are located in the middle of TM2, TM3, TM6 or TM7, while a substantially narrower number of highly connected residues are located in the middle of TM1, TM4 or TM5. There are no substantial differences in the pool of residues with the highest centrality in the seven analyzed structures. The only notable exception concerns the activated structure (3P0G), for which residues located toward the cytosolic end of the middle portion of TM6 show a lower centrality when compared to their counterparts in the inactive structures.Figure 7

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