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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 GABAB receptor family
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
Golf 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
- 30-40 residues
- interaction with receptor over large surface area
family 3: mGluR/GABAB family. describe
- 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
- forms dimers
GABAB receptor forms ...
- deterodimers between GABAB R1 and GABABR2 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
- heterotrimeric G-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?