4MQS: Structure Of Active Human M2 Muscarinic Acetylcholine Receptor Bound To The Agonist Iperoxo

Citation:
Abstract
Despite recent advances in crystallography and the availability of G-protein-coupled receptor (GPCR) structures, little is known about the mechanism of their activation process, as only the beta2 adrenergic receptor (beta2AR) and rhodopsin have been crystallized in fully active conformations. Here we report the structure of an agonist-bound, active state of the human M2 muscarinic acetylcholine receptor stabilized by a G-protein mimetic camelid antibody fragment isolated by conformational selection using yeast surface display. In addition to the expected changes in the intracellular surface, the structure reveals larger conformational changes in the extracellular region and orthosteric binding site than observed in the active states of the beta2AR and rhodopsin. We also report the structure of the M2 receptor simultaneously bound to the orthosteric agonist iperoxo and the positive allosteric modulator LY2119620. This structure reveals that LY2119620 recognizes a largely pre-formed binding site in the extracellular vestibule of the iperoxo-bound receptor, inducing a slight contraction of this outer binding pocket. These structures offer important insights into the activation mechanism and allosteric modulation of muscarinic receptors.
PDB ID: 4MQSDownload
MMDB ID: 115516
PDB Deposition Date: 2013/9/16
Updated in MMDB: 2013/12
Experimental Method:
x-ray diffraction
Resolution: 3.5  Å
Source Organism:
Lama glama
Similar Structures:
Biological Unit for 4MQS: dimeric; determined by author and by software (PISA)
Molecular Components in 4MQS
Label Count Molecule
Proteins (2 molecules)
1
Muscarinic Acetylcholine Receptor M2(Gene symbol: CHRM2)
Molecule annotation
1
Nanobody 9-8
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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