| Literature References | 1. ATTWOOD, T.K. AND FINDLAY, J.B.C.
Fingerprinting G protein-coupled receptors.
PROTEIN ENG. 7(2) 195-203 (1994).
2. ATTWOOD, T.K. AND FINDLAY, J.B.C.
G protein-coupled receptor fingerprints.
7TM, VOLUME 2, EDS. G.VRIEND AND B.BYWATER (1993).
3. BIRNBAUMER, L.
G proteins in signal transduction.
ANNU.REV.PHARMACOL.TOXICOL. 30 675-705 (1990).
4. CASEY, P.J. AND GILMAN, A.G.
G protein involvement in receptor-effector coupling.
J.BIOL.CHEM. 263(6) 2577-2580 (1988).
5. ATTWOOD, T.K. AND FINDLAY, J.B.C.
Design of a discriminating fingerprint for G protein-coupled receptors.
PROTEIN ENG. 6(2) 167-176 (1993).
6. WATSON, S. AND ARKINSTALL,
Adenosine and adenine nucleotides.
IN THE G PROTEIN-LINKED RECEPTOR FACTSBOOK, ACADEMIC PRESS, pp19-31.
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| Documentation | G protein-coupled receptors (GPCRs) constitute a vast protein family that
encompasses a wide range of functions (including various autocrine, para-
crine and endocrine processes). They show considerable diversity at the
sequence level, on the basis of which they can be separated into distinct
groups. We use the term clan to describe the GPCRs, as they embrace a group
of families for which there are indications of evolutionary relationship,
but between which there is no statistically significant similarity in
sequence [1]. The currently known clan members include the rhodopsin-like
GPCRs, the secretin-like GPCRs, the cAMP receptors, the fungal mating
pheromone receptors, and the metabotropic glutamate receptor family.
The rhodopsin-like GPCRs themselves represent a widespread protein family
that includes hormone, neurotransmitter and light receptors, all of
which transduce extracellular signals through interaction with guanine
nucleotide-binding (G) proteins. Although their activating ligands vary
widely in structure and character, the amino acid sequences of the
receptors are very similar and are believed to adopt a common structural
framework comprising 7 transmembrane (TM) helices [3-5].
In addition to their role in energy metabolism, purines (especially
adenosine and adenine nucleotides) produce a wide range of pharmacological
effects mediated by activation of cell surface receptors [6]. Distinct
receptors exist for adenosine. In the periphery, the main effects of
adenosine include vasodilation, bronchoconstriction, immunosuppresion,
inhibition of platelet aggregation, cardiac depression, stimulation of
nociceptive afferents, inhibition of neurotransmitter release and
inhibition of the release of other factors, e.g. hormones [6]. In the CNS,
adenosine exerts a pre- and post-synaptic depressant action, reducing motor
activity, depressing respiration, inducing sleep and relieving anxiety. The
physiological role of adenosine is thought to be to adjust energy demands
in line with oxygen supply. Many of the clinical actions of methylxanthines
are thought to be mediated through antagonism of adenosine receptors. Four
subtypes of receptor have been identified, designated A1, A2A, A2B and A3.
A2A receptors have a limited distribution in the brain and are found in the
striatum, olfactory tubercle and nucleus accumbens. In the periphery, A2
receptors mediate vasodilation, immunosuppression, inhibition of platelet
aggregation and gluconeogenesis [6]. The receptors activate adenylyl
cyclase through Gs.
ADENOSINA2AR is an 8-element fingerprint that provides a signature for the
A2A family of adenosine receptors. The fingerprint was derived from an
initial alignment of 6 sequences: the motifs were drawn from conserved
sections within either loop or C-terminal regions, focusing on those areas
of the alignment that characterise the adenosine A2A receptors but
distinguish them from the rest of the rhodopsin-like superfamily - motif 1
spans the C-terminus of TM domain 1, leading into the first cytoplasmic
loop; motif 2 lies in the first external loop; motif 3 lies in the second
external loop; motif 4 lies in the third cytoplasmic loop; motif 5 lies in
the third external loop; and motifs 6-8 span the C-terminus. A single
iteration on OWL28.1 was required to reach convergence, no further sequences
being identified beyond the starting set. A single partial match was also
found, I48932, a mouse adenosine receptor fragment that matches motifs 2
and 3.
An update on SPTR37_9f identified a true set of 5 sequences.
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