2.2.5 Remark2
Transmission is possible if A and B have some internal flexibility
(i.e., DOF
A and DOF
B
> 0).
2.2.6 Remark3
Uniqueness and correctness of the DOF
AB counts extracted from
RTA algorithm, the pebble game extensions that allow fast computations of counts in step 1 and 3, and the relevant region detection
algorithm for detection of allosteric are mathematically verified [8].
Extensions of this work (to appear) will show how to accurately
map out the pathways that correlate with NMR experimental measures for probing allosteric crosstalk.
2.3 Case
Study: GPCR
We will illustrate the RTA method on human adenosine A 2A receptor, a G protein coupled receptor (GPCR). GPCRs are the largest
class of receptors in the human genome [29–34]. The rhodopsin
family of G protein coupled receptors (GPCRs), also known as
family A GPCR, represents over 80% of all GPCRs. Humans have
over 800 unique GPCRs, which are characterized by the same
underlying topology consisting of 7-transmembrane alpha-helices.
GPCRs mediate most transmembrane signal transduction by
responding to an enormous variety of extracellular stimuli (drugs,
hormones, neurotransmitters, ions, proteins, etc.) as well as senses
of sight, olfaction, and taste. GPCRs also play an important role in
disease and drug discovery with around 50% of all modern medicinal drugs targeting GPCRs [2, 30, 31, 34].
GPCRs are typically regulated by extracellular ligands called
agonists. Agonists and inactivating ligands antagonists or inverse
agonists usually bind at the similar location at the extracellular
region (i.e., orthorsteric pocket) of the receptor and activation
can be further increased or decreased through interactions with
allosteric modulators that bind at different sites from the orthorsteric site and also residue specific mutations [30, 31]. Agonist
binding induces a subtle conformational change within the binding
pocket, which causes relative movement of α-helices and a
subsequent larger change in conformation at the intracellular side
of the receptor [31, 32]. This enables activation of GPCR and
binding to its G protein partner, leading to exchange of GDP and
GTP, dissociation of the G protein into an α-subunit and a βγ-subunit and subsequent activation of additional downstream
partners.
A significant movement and conformational change at the
cytoplasmic end of TM helix 6 is believed to be central in GPCR
activation together with smaller rearrangement of TM3, TM5 and
TM7 [30–32]. GPCRs are naturally allosteric as orthrosteric site
and G protein binding region crosstalk must travers over large
distance, spanning the TM region. As is the case with many dynamics proteins, GPCRs do not function through simple on and off
switches. GPCRs are highly dynamic and can adopt a multiple of
conformational ensemble states which are normally categorized as:
70
Adnan Sljoka
Transmission is possible if A and B have some internal flexibility
(i.e., DOF
A and DOF
B
> 0).
2.2.6 Remark3
Uniqueness and correctness of the DOF
AB counts extracted from
RTA algorithm, the pebble game extensions that allow fast computations of counts in step 1 and 3, and the relevant region detection
algorithm for detection of allosteric are mathematically verified [8].
Extensions of this work (to appear) will show how to accurately
map out the pathways that correlate with NMR experimental measures for probing allosteric crosstalk.
2.3 Case
Study: GPCR
We will illustrate the RTA method on human adenosine A 2A receptor, a G protein coupled receptor (GPCR). GPCRs are the largest
class of receptors in the human genome [29–34]. The rhodopsin
family of G protein coupled receptors (GPCRs), also known as
family A GPCR, represents over 80% of all GPCRs. Humans have
over 800 unique GPCRs, which are characterized by the same
underlying topology consisting of 7-transmembrane alpha-helices.
GPCRs mediate most transmembrane signal transduction by
responding to an enormous variety of extracellular stimuli (drugs,
hormones, neurotransmitters, ions, proteins, etc.) as well as senses
of sight, olfaction, and taste. GPCRs also play an important role in
disease and drug discovery with around 50% of all modern medicinal drugs targeting GPCRs [2, 30, 31, 34].
GPCRs are typically regulated by extracellular ligands called
agonists. Agonists and inactivating ligands antagonists or inverse
agonists usually bind at the similar location at the extracellular
region (i.e., orthorsteric pocket) of the receptor and activation
can be further increased or decreased through interactions with
allosteric modulators that bind at different sites from the orthorsteric site and also residue specific mutations [30, 31]. Agonist
binding induces a subtle conformational change within the binding
pocket, which causes relative movement of α-helices and a
subsequent larger change in conformation at the intracellular side
of the receptor [31, 32]. This enables activation of GPCR and
binding to its G protein partner, leading to exchange of GDP and
GTP, dissociation of the G protein into an α-subunit and a βγ-subunit and subsequent activation of additional downstream
partners.
A significant movement and conformational change at the
cytoplasmic end of TM helix 6 is believed to be central in GPCR
activation together with smaller rearrangement of TM3, TM5 and
TM7 [30–32]. GPCRs are naturally allosteric as orthrosteric site
and G protein binding region crosstalk must travers over large
distance, spanning the TM region. As is the case with many dynamics proteins, GPCRs do not function through simple on and off
switches. GPCRs are highly dynamic and can adopt a multiple of
conformational ensemble states which are normally categorized as:
70
Adnan Sljoka