4mqt

Structure of active human M2 muscarinic acetylcholine receptor bound to the agonist iperoxo and allosteric modulator LY2119620

spinqualitylabelsall models 4mqt, resolution 3.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4mqt is a 2 chain structure with sequence from Homo sapiens and Lama glama. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.7Å Ligands: 2CU, IXO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease ACM2_HUMAN Disease susceptibility is associated with variations affecting the gene represented in this entry. Function ACM2_HUMAN The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is adenylate cyclase inhibition. Publication Abstract from PubMed 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. Activation and allosteric modulation of a muscarinic acetylcholine receptor.,Kruse AC, Ring AM, Manglik A, Hu J, Hu K, Eitel K, Hubner H, Pardon E, Valant C, Sexton PM, Christopoulos A, Felder CC, Gmeiner P, Steyaert J, Weis WI, Garcia KC, Wess J, Kobilka BK Nature. 2013 Nov 20. doi: 10.1038/nature12735. PMID:24256733 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Muscarinic acetylcholine receptor

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