Avidin
This is a protein expressed in avian eggs (egg white), which func;ons to sequester the vitamin bio;n so that bacteria can’t use it and grow inside the egg.
Has a femtomolar KD for biotin.
KD rate definition
koff/k<span>on</span>
Fractional saturation
How fractional saturation curves vary with KD
Standard free energy of binding
GPCR Overview
GPCRs provide the sensors for. . .
Light, smell, and taste
In the case of light, the GPCRs contain a photosensitive ligand (retinal) that isomerizes when light strikes the retina. In the case of smell, odorant molecules (volatile chemicals) bind to GPCRs in cells in the epithelium lining the nasal cavity, simula;ng nerves that sense smell. In the tongue, taste buds contain specialized cells with GPCRs that bind to molecules in food.
“orphan” receptors
GPCRs whose function we do not yet understand, or for which no ligand is yet known
metabotropic receptors
In the nervous system, as distinguished from ionotropic receptors, metabotropic receptors signal via metabolic effects such as GTP hydrolysis. (Most are GPCRs)
Effects of GPCR signaling may be longer lasting and affect different signaling pathways than those triggered by activation of ionotropic receptors.
Signaling GPCR families
The most studied GPCR family is made up of acetylcholine receptors. The rest are as follow:
Sensation GPCR families
GPCR Signaling Sketch
Structure of a GPCR
The loops are labeled “C” if they are on the cytoplasmic face and “E” if they are on the extracellular (exoplasmic) face. Labeled here are loops C1, C2, and E2; C3, E1, and E3 are not labeled. The small molecule ligand makes contacts with the transmembrane helices as well as the E2 loop
GPCR cycle
An agonist binds the receptor in a way that. . .
allows it to adopt a conformation that can bind and activate the Gprotein.
“On” vs “Off” G protein conformation
Adenylyl Cyclase Regulation
PKA Signaling
Note that the G protein here is a Gs
cAMP
Gq PLC Pathway
PLC Activity
Major Calmodulin Targets
Arrestin-mediated GPCR inactivation
Interestingly, arrestin can also recruit proteins from other signaling pathways, and activate them
GRK
GPCR-kinase
If a cell encounters a chronically high level of ligand (or perhaps a drug that you might administer) that activates the receptor, this can lead to recognition of the GPCR by GRK. The kinase only binds and phosphorylates the receptor if the receptor is in the ligand bound state. Phosphorylation of the GPCR leads to binding of arrestin.
GPCRs are effectively. . .
ligand-dependent GEFs
IP3 vs PIP3
IP3 is generated by PLC in response to GPCR/Gaq signaling
PIP3 is generated by PI3K in response to RTK signaling
Enzyme that produces histamine
L-histidine decarboxylase
Mediates decarboxylation of histidine to form histamine.
H1 receptor binding
Causes leaky endothelium on endothelial cells.
Also present in histaminergic neurons in the brain along with H3. Here it controls wakefulness.
H2 receptor binding
Induces stomach parietal cell stimulation to release acid.
H3 receptor binding
Present in histaminergic neurons in the brain along with H1. Here it controls wakefulness.
“We are not the sum of our GPCRs”
There are many other mediators and environmental factors that may control drug efficacy.