Molecular Pharmacology - Cholinergic System Flashcards
what is the bound structure of ACh determined by
solid-state NMR
what did docking to ACHBP reveal
extensive cation-pi interactions
binding of positive charges
what does agonist binding to ACh lead to
C-loop folding over the binding pocket
what happens after C-loop wraps around the ligand
initiates rotation of beta-sandwich
what does the rotation of the beta-sandwich cause
causes the movement of Cys and beta 1 - beta 2 loops
what does movement of beta1 - beta2 loops and Cys cause
leads to release of M2 - transmembrane domain from locked state
what happens when M2-TMD is released from its locked state
rotation of alpha-subunits occurs
what does alpha-subunit rotation lead to
unlocking of the hydrophobic gate
what type of receptor is a muscarinic acetylcholine receptor
G-protein coupled receptor
where are M1 and M2 primarily located
M1 - primarily in the cerebral cortex
M2 - expressed in cardiac tissue
what is necessary for ACh binding
Hydrogen bonding
what is the function of ester and hydrophobic groups in terms of ACh structure/activity
ester - necessary for high binding affinity
hydrophobic group - drives binding
how does a removal of a hydroxyl group affect binding to ACh binding site
reduces the Kd
in the ACh binding site is the function of the ionic interactions and the aromatic cage
drives binding of the quaternary ammonia group
how would you get insight into rat M2/M3 receptor subtype specificity using X-ray structures
they are crystallised in the presence of antagonists QNB and tiotropium
