changes. In other words, the presence of an agonist in the ligand
binding pocket enables individual helices to extricate themselves
and gain flexibility, thus ultimately facilitating binding of the
G s -protein. On the other hand, presence of an antagonist compels
the helices to associate with each other (at the cytoplasmic region)
and thus makes binding of G s -protein impossible. Overall, we
observe that local changes in the ligand binding site translate to a
re-wiring of contacts at the cytoplasmic region, thus exhibiting a
characteristic allosteric response. Further, the strength of these
interactions examined in terms of side-chain edge weights also
highlights the mechanism of information flow across the TM architecture, which is discussed below.
5.2 Differences
in Edge Weights
Between
the Complexes
β 2 AR-G s
and β 2 AR-Anta
Analyzing non-covalent side-chain interactions in terms of edge
weights highlights subtle differences in the overall architecture of
the transmembrane region. Herein, we compared the agonist and
antagonist-bound β 2 AR complexes and obtained a list of interactions which differ among the compared systems by an edge weight
of 0.5 (Table 1).
5.2.1 Differences
Between β 2 AR-G s
and β 2 AR-Anta Complexes
Disengagement of individual helices in the agonist bound case has a
dramatic effect on β 2 AR to interact with G s . A closer look at edge
weight differences between β 2 AR-G s and β 2 AR-anta reveals an
interesting trend among residues that are present in the cytoplasmic
side of TMs 5 and 6 as well as the ICL2 (Fig. 4). Ideally, when the
receptor coordinates with its cognate G-protein, these residues are
recruited for establishing contacts with the α5 and αN helical
regions of G s , leading to stabilization of the complex. Here, we
highlight certain examples from our findings that illustrate a change
in the behavior of these bridging residues. First, Ser143 (ICL2)
forms strong residue contacts with Asp130
3.49 and Val67
2.38 in
β 2 AR-anta (edge weights 0.75 and 1.00 respectively). In the
G-protein bound complex the same residue, i.e., Ser143 (ICL2),
coordinates via its OG atom and forms intermolecular interaction
with the Ala139 (CB) in the αN helix. Second, Gln229
5.68 interacts
with a high edge weight with Lys140 (ICL2) in the β 2 AR-anta
(edge weight 0.75). In the G-protein bound complex β 2 AR-G s , it
establishes contacts with a network of residues (Asp381, Gln384,
Arg385 and Leu388) present in the α5 helical region. Third, in
β 2 AR-anta, His269
6.31 forms an interaction with Ala226
5.65 (edge
weight 0.67). But Ala226
5.65 from the receptor interacts with
Leu388 and Leu393 from the α5 region of G-protein in the
G-protein bound complex. From these cases, we postulate that
residues from the interface region are coerced into forming intramolecular interactions rather than getting involved in interNetwork Re-Wiring During Allostery and PPI
101
binding pocket enables individual helices to extricate themselves
and gain flexibility, thus ultimately facilitating binding of the
G s -protein. On the other hand, presence of an antagonist compels
the helices to associate with each other (at the cytoplasmic region)
and thus makes binding of G s -protein impossible. Overall, we
observe that local changes in the ligand binding site translate to a
re-wiring of contacts at the cytoplasmic region, thus exhibiting a
characteristic allosteric response. Further, the strength of these
interactions examined in terms of side-chain edge weights also
highlights the mechanism of information flow across the TM architecture, which is discussed below.
5.2 Differences
in Edge Weights
Between
the Complexes
β 2 AR-G s
and β 2 AR-Anta
Analyzing non-covalent side-chain interactions in terms of edge
weights highlights subtle differences in the overall architecture of
the transmembrane region. Herein, we compared the agonist and
antagonist-bound β 2 AR complexes and obtained a list of interactions which differ among the compared systems by an edge weight
of 0.5 (Table 1).
5.2.1 Differences
Between β 2 AR-G s
and β 2 AR-Anta Complexes
Disengagement of individual helices in the agonist bound case has a
dramatic effect on β 2 AR to interact with G s . A closer look at edge
weight differences between β 2 AR-G s and β 2 AR-anta reveals an
interesting trend among residues that are present in the cytoplasmic
side of TMs 5 and 6 as well as the ICL2 (Fig. 4). Ideally, when the
receptor coordinates with its cognate G-protein, these residues are
recruited for establishing contacts with the α5 and αN helical
regions of G s , leading to stabilization of the complex. Here, we
highlight certain examples from our findings that illustrate a change
in the behavior of these bridging residues. First, Ser143 (ICL2)
forms strong residue contacts with Asp130
3.49 and Val67
2.38 in
β 2 AR-anta (edge weights 0.75 and 1.00 respectively). In the
G-protein bound complex the same residue, i.e., Ser143 (ICL2),
coordinates via its OG atom and forms intermolecular interaction
with the Ala139 (CB) in the αN helix. Second, Gln229
5.68 interacts
with a high edge weight with Lys140 (ICL2) in the β 2 AR-anta
(edge weight 0.75). In the G-protein bound complex β 2 AR-G s , it
establishes contacts with a network of residues (Asp381, Gln384,
Arg385 and Leu388) present in the α5 helical region. Third, in
β 2 AR-anta, His269
6.31 forms an interaction with Ala226
5.65 (edge
weight 0.67). But Ala226
5.65 from the receptor interacts with
Leu388 and Leu393 from the α5 region of G-protein in the
G-protein bound complex. From these cases, we postulate that
residues from the interface region are coerced into forming intramolecular interactions rather than getting involved in interNetwork Re-Wiring During Allostery and PPI
101