5afj

alpha7-AChBP in complex with lobeline and fragment 1

spinqualitylabelsall models 5afj, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5afj is a 5 chain structure with sequence from Homo sapiens and Lymnaea stagnalis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 42R, BMA, GOL, L0B, MAN, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease ACHA7_HUMAN 15q13.3 microdeletion syndrome. Function ACHP_LYMST Binds to acetylcholine. Modulates neuronal synaptic transmission.ACHA7_HUMAN After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. The channel is blocked by alpha-bungarotoxin. Publication Abstract from PubMed The alpha7 nicotinic acetylcholine receptor (nAChR) belongs to the family of pentameric ligand-gated ion channels and is involved in fast synaptic signaling. In this study, we take advantage of a recently identified chimera of the extracellular domain of the native alpha7 nicotinic acetylcholine receptor and acetylcholine binding protein, termed alpha7-AChBP. This chimeric receptor was used to conduct an innovative fragment-library screening in combination with X-ray crystallography to identify allosteric binding sites. One allosteric site is surface-exposed and is located near the N-terminal alpha-helix of the extracellular domain. Ligand binding at this site causes a conformational change of the alpha-helix as the fragment wedges between the alpha-helix and a loop homologous to the main immunogenic region of the muscle alpha1 subunit. A second site is located in the vestibule of the receptor, in a preexisting intrasubunit pocket opposite the agonist binding site and corresponds to a previously identified site involved in positive allosteric modulation of the bacterial homolog ELIC. A third site is located at a pocket right below the agonist binding site. Using electrophysiological recordings on the human alpha7 nAChR we demonstrate that the identified fragments, which bind at these sites, can modulate receptor activation. This work presents a structural framework for different allosteric binding sites in the alpha7 nAChR and paves the way for future development of novel allosteric modulators with therapeutic potential. Molecular blueprint of allosteric binding sites in a homologue of the agonist-binding domain of the alpha7 nicotinic acetylcholine receptor.,Spurny R, Debaveye S, Farinha A, Veys K, Vos AM, Gossas T, Atack J, Bertrand S, Bertrand D, Danielson UH, Tresadern G, Ulens C Proc Natl Acad Sci U S A. 2015 Apr 27. pii: 201418289. PMID:25918415 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Acetylcholine binding protein 3D structures

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