Activation and allosteric modulation of a muscarinic acetylcholine receptor
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Figure: M2 muscarinic receptor
(orange) bound to the agonist iperoxo (blue) and the positive allosteric
modulator LY2119620 (green). |
Brian Kobilka group (Stanford University) and collaborators
The groups of Brian Kobilka, Bill Weis, and Chris Garcia at
Stanford University investigated both activation and allosteric modulation of
a muscarinic acetylcholine receptor. Muscarinic acetylcholine receptors (M1
- M5) are GPCRs that regulate the activity of a diverse array of central and
peripheral functions in the human body, including the parasympathetic actions
of acetylcholine. The M2 muscarinic receptor subtype plays a key role in
modulating cardiac function and many important central processes such as
cognition and pain perception. As it was among the first GPCRs to be cloned
and purified, the M2 receptor has long served as a model system in GPCR
biology and pharmacology. Muscarinic receptors have attracted particular
interest due to their ability to bind small molecule allosteric modulators.
Since allosteric sites are often less conserved than the orthosteric binding
site, some ligands binding to allosteric sites show substantial subtype
selectivity. To better understand how allosteric ligands regulate GPCR
function, the group solved structures of an active-state human M2 muscarinic
acetylcholine receptor bound to an agonist alone and bound to an agonist
together with a positive allosteric modulator. The active state was
stabilized by a G-protein mimetic antibody fragment. In addition to expected
changes in the intracellular surface, the structure of the agonist-bound M2
receptor reveals larger conformational changes in the extracellular surface
and the orthosteric binding site than observed in the active states of the
beta 2 adrenergic receptor and rhodopsin. The structure of the M2 receptor
ternary complex with an orthosteric agonist and a positive allosteric
modulator reveals that the modulator recognizes a largely pre-formed binding
site in the extracellular vestibule of the agonist-bound receptor. These
structures offer important insights into activation mechanism and allosteric
modulation of muscarinic receptors.
Citation: Kruse, AC, Ring, AM, Manglik, A, Hu, J, Hu, K,
Eitel, K, H?bner, H, Pardon, E, Valant, C, Sexton, PM, Christopoulos, A,
Felder, CC, Gmeiner, P, Steyaert, J, Weis, WI, Garcia, KC, Wess, J, Kobilka ,
BK. Activation and allosteric modulation of a muscarinic acetylcholine
receptor, Nature 504, 101-106 (2013). DOI: 10.1038/nature12735
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