Card Set Information
GPCR superfamily is considered...
the largest known receptor family
constitutes more than 1% of the human genome
what does GPCR comprises receptors of?
a diverse array of molecules:
nt, odorants, lipids, neuropeptides, large glycoprotein hormones
odorant receptor family alone contains 100s of genes
what are the mammalian GPCR? any subfamilies?
nearly 300 diff. kinds
3 main subfamilies:
1. Rhodopsin-like group (most of GPCRs)
2. Glucagon-like pump
Metabotropic glutamate (mGli) and GABA
how are the 3 subfamilies grouped?
according to >20% of sequence homology
what are orphan receptors?
each GPCR family contains this
ID as membrans of GPCR superfamily by homology cloning but activating ligand is unknown
what does α contains?
contains GTP/GDP binding site which is responsible for identity
β and γ subunits are...
identical in vitro; most are ubiquitously expressed; anchor thru prenylation of Gβ
are exprssed in...
olfactory bulb, coupled to PLCβ
coupled to cGMP phosphodiesterase and expressed in rod cells of retina
cells inactivate by light
Where are the N terminal and the C terminal located?
N terminal located on extracellular and C terminal on the intracellular
Glucagon-like family. describe them
structurally similar to family 1, except larger N terminal domain (contains multiple potential S-S bridges)
most ligands binding to receptors are peptides or glycprotein hormones
interaction with receptor over large surface area
family 3: mGluR/GABA
extremely large extraceullar N terminal ligand binding domain
highly ocnserved 3rd short intracellular loop
shares ~12% sequence homology with that of family 1, but overall transmembrane topology is similar
receptor forms ...
deterodimers between GABA
R1 and GABA
R2 thru coiled regions in C-terminal tails
required for effiicient cell surface expression and signalling
How is metabotropic glutamate receptors dimerization stabilized?
by disulfide bonds in N terminal extracellular domain
What is GPCR?
larger family of receptorswith prbable common evolutionary precursor. transmembrane protein that is serpentine in shape, crossing lipid bilayer 7x
7 transmembrane domain
G proteins are...
Guanine nucleotide binding proteins;
in GTP mediated interactions
common feature of G protein
bind GDP and GTP with high affinity, but
GTP bound complex - high affinity for other proteins, affect enzymatic activity
possess intrinsic GTPase activity thats activated by interaction with regulatory proteins (GAPs)
GTPae activating proteins, that function on small GTP binding proteins
Guanine-nucleotide Exchange Factors that promote GDP release
regulations of G-protein signaling, similar to GAPs but act on heterotrimeric G proteins
G protein, common way to bind to GTP
myristoylation, palmitoylation; linked to phospholipid tails (or lipid rafts)
what are the major groups of G proteins?
small GTP binding proteins
small GTP binding proteins
act downstream of receptor
: ras, rac, etc
growth ffactor receptor signaling?
directly coupled to receptor and enzyme
coupled to 7 transmembrane spanning receptors
all are heterotrimeric, consist of α, β, and γ subunits
How does using toxins (or getting rid of it) helps?
causes ADP-ribosylation of Gα, then release of GTP inhibited, then Gα trapped in active form. cAMP regulates secretion of fluid to intestinum, enormous loss of liquid and electrolytes = death
cuases ADP ribosylation of Gα release of GDP inhibit, the Gα locked in inactive form, then cant inhibit AC
drug-receptor interaction is?
agonists vary in binding affinity for GPCR
how well drug causes conformational change in receptor to activate G proteins
what type of agonists are there?
partial or full with different binding affinities
**agonist causes inactivation
mechanism of conformation change?
is highly conserved
contraining intermolecular interactions that keep receptors preferentially silent in absence of agonist, between TM5&6, and between TM3&7
eg. DRY motif in TM3
what happens upon receptor activation?
arg is proteinated
adjacent resides move
tiliting the TM helix
increase exposes previously hidden sequences, which interact with G protein
***exact aa sequence responsible - difficult to pinpoint
REFER back to slides?