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paths between the extracellular and intracellular sides in both functional states,
with emphasis on the active one (
Angelova et al., 2011
). As for the A
2A
R, the dy-
namic network of intramolecular interactions characterizing the complex with the
ZM241385 (i.e., ZMA) antagonist in its monomeric state was compared with that
of the same complex in three different dimericforms,aswellaswiththatofthe
apo-protomer. The results of the studyemphasizedtherolesofH1inA
2A
Rhomo-
dimerizationandofhighlyconservedaminoacidsinH1,H2,H6,andH7inmain-
taining the structure network of the A
2A
R. A
2A
R dimerization resulted to affect the
communication networks intrinsic to the receptor fold in a way dependent on the
dimer architecture. Certain architectures retained the most recurrent communica-
tion paths with respect to the monomeric antagonist-bound form but enhancing
path numbers and frequencies, whereas some others impaired ligand-mediated
communication. Ligand binding turned out to affect the network as well. Collec-
tively, the study suggested that the communication network that pertains to the
functional dynamics of a GPCR is influenced by ligand functionality, oligomeric
order, and architecture of the supramolecular assembly.
The results discussed above were achieved by the PSN-MD approach. We have
recently undertaken a comparative PSN analysis on all the GPCR crystallographic
structures released so far by the PSN-ENM approach (manuscript in preparation).
The goal of the study is to infer functional state-dependent and state-independent
commonalties and differences in the structural communication features at the
family and subfamily levels. Herein, the case study of dark rhodopsin and MII
has been extracted from that analysis to show what PSN analysis, carried out on a
single structure, can tell us in terms of network differences between inactive and
active states.
The structure networks of dark and MII states of rhodopsin are quite similar in
number of nodes, hubs, links, and hub-mediated links (
Table 3.1
); the only difference
is that the number of links is slightly higher in the inactive than the active state, con-
sistent with the higher stability of the former (
Khan, Bole, Hargrave, Santoro, &
McDowell, 1991
). In spite of numerical similarities in network parameters, up to
57% of links and less than 50% of hubs and link-mediated hubs are shared in com-
mon by the two forms (
Table 3.1
). Major differences in the PSG concern the retinal
chromophore, which acts as a hub in both forms. However, whereas 11-cis-retinal is
part of a network community, all-trans-retinal is not (
Fig. 3.2
). Incidentally, commu-
nities are sets of highly interconnected vertices such that nodes belonging to the same
community are densely linked to each other and poorly connected to nodes outside
the community. Thus, photoactivated retinal is involved in a less dense network com-
pared to the 11-cis form. Remarkably, in the dark state, retinal interacts with nodes in
three different communities. This is suggestive of retinal and the extracellular re-
gions making a dense network likely involved in the stability of the protein. Such
network does not occur in the MII state (
Figs. 3.2 and 3.3
). Collectively, the receptor
portions that hold major specificity in links between inactive and active states in-
clude H2, H3, E2, H6, and H7 (
Fig. 3.3
). Structural water molecules participate
in such differences as well.
