The clustering of nodes is uniquely obtained from graph spectral decomposition on a network which involves obtaining eigen
values and eigen vectors of Laplacian matrix of the network.
Nodes of the same cluster have closer numerical values in the
Fiedler vector components. Therefore, sorted Fiedler vector components are used to obtain node clustering in the network. A
flowchart describing this methodology is depicted in Fig. 1.
A holistic understanding of an allosteric system can be obtained
by analyzing edge weights and node clustering using weighted
PSNs. This is illustrated below in the case of a protein complex
with a well-characterized biological activity.
5 Case Study of β 2 Adrenergic Receptors
We apply the methodology discussed above to understand the
mechanism of signal transduction that involves transmission of
chemical or physical signals through the cell, triggering a characteristic cellular response. Herein, we focus on the archetypal transmembrane (TM) signaling molecules i.e., G-Protein Coupled
Receptors (GPCRs), which possess extraordinary potential to
respond to a diverse set of extracellular stimuli like light, ions,
hormones, neurotransmitters, and small molecule ligands and
thereby mediate cellular signaling by interacting with heterotrimeric GTP-binding proteins (G-proteins) [33]. At the heart of
this signaling cascade lies the ligand-dependent activation of
GPCRs, followed by G-protein coupling and nucleotide exchange
that eventually culminates in regulation of downstream effector
proteins [34]. GPCRs function by means of ligand-driven activation followed by conformational changes that mediate interaction
with GDP-bound G-protein heterotrimers (G αβγ ). Nucleotide
exchange and the subsequent dissociation of G βγ from G α result
in regulating the activities of cellular effectors like kinases, ion
channels, and other enzymes. GPCRs control a variety of physiological processes that include sense of smell, taste, sight as well as
immune response, behavior, autonomous nervous system transmission, and homoeostasis modulation [35, 36]. Their implication in
numerous biological phenomena thus warrants an understanding
of intricacies in their three-dimensional molecular structure [37].
X-ray crystallography–based experimental studies offer highresolution atomistic details on molecular structure of GPCRs.
Details from the three-dimensional structure can be used to explain
effects of GPCRs in response to a diverse array of small molecule
ligands. These ligands bind to the GPCRs at conserved or orthosteric binding site located at the core of their seven-helical transmembrane (7TM) region. Discrete classes of ligands include those
that maximally activate the receptor (agonists), induce sub-optimal
activity (partial agonists), inhibit basal activity (inverse agonists),
96
Vasundhara Gadiyaram et al.
values and eigen vectors of Laplacian matrix of the network.
Nodes of the same cluster have closer numerical values in the
Fiedler vector components. Therefore, sorted Fiedler vector components are used to obtain node clustering in the network. A
flowchart describing this methodology is depicted in Fig. 1.
A holistic understanding of an allosteric system can be obtained
by analyzing edge weights and node clustering using weighted
PSNs. This is illustrated below in the case of a protein complex
with a well-characterized biological activity.
5 Case Study of β 2 Adrenergic Receptors
We apply the methodology discussed above to understand the
mechanism of signal transduction that involves transmission of
chemical or physical signals through the cell, triggering a characteristic cellular response. Herein, we focus on the archetypal transmembrane (TM) signaling molecules i.e., G-Protein Coupled
Receptors (GPCRs), which possess extraordinary potential to
respond to a diverse set of extracellular stimuli like light, ions,
hormones, neurotransmitters, and small molecule ligands and
thereby mediate cellular signaling by interacting with heterotrimeric GTP-binding proteins (G-proteins) [33]. At the heart of
this signaling cascade lies the ligand-dependent activation of
GPCRs, followed by G-protein coupling and nucleotide exchange
that eventually culminates in regulation of downstream effector
proteins [34]. GPCRs function by means of ligand-driven activation followed by conformational changes that mediate interaction
with GDP-bound G-protein heterotrimers (G αβγ ). Nucleotide
exchange and the subsequent dissociation of G βγ from G α result
in regulating the activities of cellular effectors like kinases, ion
channels, and other enzymes. GPCRs control a variety of physiological processes that include sense of smell, taste, sight as well as
immune response, behavior, autonomous nervous system transmission, and homoeostasis modulation [35, 36]. Their implication in
numerous biological phenomena thus warrants an understanding
of intricacies in their three-dimensional molecular structure [37].
X-ray crystallography–based experimental studies offer highresolution atomistic details on molecular structure of GPCRs.
Details from the three-dimensional structure can be used to explain
effects of GPCRs in response to a diverse array of small molecule
ligands. These ligands bind to the GPCRs at conserved or orthosteric binding site located at the core of their seven-helical transmembrane (7TM) region. Discrete classes of ligands include those
that maximally activate the receptor (agonists), induce sub-optimal
activity (partial agonists), inhibit basal activity (inverse agonists),
96
Vasundhara Gadiyaram et al.