5t90 | pdb_00005t90

Structural mechanisms for alpha-conotoxin selectivity at the human alpha3beta4 nicotinic acetylcholine receptor

spinqualitylabelsall models 5t90, resolution 2.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5t90 is a 10 chain structure with sequence from Conus and Lymnaea stagnalis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.8Å Ligands: NH2 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function ACHP_LYMST Binds to acetylcholine. Modulates neuronal synaptic transmission. Publication Abstract from PubMed Nicotinic acetylcholine receptors (nAChR) are therapeutic targets for a range of human diseases. alpha-Conotoxins are naturally occurring peptide antagonists of nAChRs that have been used as pharmacological probes and investigated as drug leads for nAChR related disorders. However, alpha-conotoxin interactions have been mostly characterised at the alpha7 and alpha3beta2 nAChRs, with interactions at other subtypes poorly understood. This study provides novel structural insights into the molecular basis for alpha-conotoxin activity at alpha3beta4 nAChR, a therapeutic target where subtype specific antagonists have potential to treat nicotine addiction and lung cancer. A co-crystal structure of alpha-conotoxin LsIA with Lymnaea stagnalis acetylcholine binding protein guided the design and functional characterisations of LsIA analogues that identified the minimum pharmacophore regulating alpha3beta4 antagonism. Interactions of the LsIA R10F with beta4 K57 and the conserved -NN- alpha-conotoxin motif with beta4 I77 and I109 conferred alpha3beta4 activity to the otherwise inactive LsIA. Using these structural insights, we designed LsIA analogues with alpha3beta4 activity. This new understanding of the structural basis of protein-protein interactions between alpha-conotoxins and alpha3beta4 may help rationally guide the development of alpha3beta4 selective antagonists with therapeutic potential. Structural mechanisms for alpha-conotoxin activity at the human alpha3beta4 nicotinic acetylcholine receptor.,Abraham N, Healy M, Ragnarsson L, Brust A, Alewood PF, Lewis RJ Sci Rep. 2017 Mar 31;7:45466. doi: 10.1038/srep45466. PMID:28361878 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Acetylcholine binding protein 3D structures

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