2mdq

A Novel 4/7-Conotoxin LvIA from Conus lividus that Selectively Blocks 3 2 vs. 6/3 2 3 Nicotinic Acetylcholine Receptors

spinqualitylabelsall models 2mdq Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2mdq is a 1 chain structure with sequence from Conus lividus. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Solution NMR, 20 models Ligands: NH2 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function CA1A_CONLI Alpha-conotoxins act on postsynaptic membranes, they bind to the nicotinic acetylcholine receptors (nAChR) and thus inhibit them. This toxin blocks alpha-3-beta-2/CHRNA3-CHRNB2 nAChR with high selectivity (IC(50)=8.67 nM (on rat) and 17.5 (on human)) (PubMed:24398291). Has also weaker activity on alpha-6/alpha-3-beta-2-beta-3 (CHRNA6/CHRNA3-CHRNB2-CHRNB3) (IC(50)=108 nM (on rat)), alpha-6/alpha-3-beta-4 (CHRNA6/CHRNA3-CHRNB4) (IC(50)=121 nM (on rat)), alpha-3-beta-4 (CHRNA3-CHRNB4) (IC(50)=148 nM (on rat)), and alpha-7/CHRNA7 nAChRs (IC(50)=3000 nM (on rat)) (PubMed:24398291). When tested on mouse with hot-plate tests, this toxin significantly increases the base pain threshold and shows analgesic effects (PubMed:26742048). Publication Abstract from PubMed This study was performed to discover and characterize the first potent alpha3beta2-subtype-selective nicotinic acetylcholine receptor (nAChR) ligand. A novel alpha4/7-conotoxin, alpha-CTxLvIA, was cloned from Conus lividus. Its pharmacological profile at Xenopus laevis oocyte-expressed rat nAChR subtypes was determined by 2-electrode voltage-clamp electrophysiology, and its 3-dimensional (3D) structure was determined by NMR spectroscopy. alpha-CTx LvIA is a 16-aa C-terminally-amidated peptide with 2-disulfide bridges. Using rat subunits expressed in Xenopus oocytes, we found the highest affinity of alpha-CTxLvIA was for alpha3beta2 nAChRs (IC50 8.7 nM), where blockade was reversible within 2 min. IC50 values were >100 nM at alpha6/alpha3beta2beta3, alpha6/alpha3beta4, and alpha3beta4 nAChRs, and >/=3 muM at all other subtypes tested. alpha3beta2 vs. alpha6beta2 subtype selectivity was confirmed for human-subunit nAChRs with much greater preference (300-fold) for alpha3beta2 over alpha6beta2 nAChRs. This is the first alpha-CTx reported to show high selectivity for human alpha3beta2 vs. alpha6beta2 nAChRs. alpha-CTxLvIA adopts two similarly populated conformations water: one (assumed to be bioactive) is highly structured, whereas the other is mostly random coil in nature. Selectivity differences with the similarly potent, but less selective, alpha3beta2 nAChR antagonist alpha-CTx PeIA probably reside within the three residues, which differ in loop 2, given their otherwise similar 3D structures. alpha4/7-CTx LvIA is a new, potent, selective alpha3beta2 nAChR antagonist, which will enable detailed studies of alpha3beta2 nAChR structure, function, and physiological roles.-Luo, S., Zhangsun, D., Schroeder, C. I., Zhu, X., Hu, Y., Wu, Y., Weltzin, M. M., Eberhard, S., Kaas, Q., Craik, D. J., McIntosh, J. M., Whiteaker, P. A novel alpha4/7-conotoxin LvIA from Conus lividus that selectively blocks alpha3beta2 vs. alpha6/alpha3beta2beta3 nicotinic acetylcholine receptors. A novel alpha4/7-conotoxin LvIA from Conus lividus that selectively blocks alpha3beta2 vs. alpha6/alpha3beta2beta3 nicotinic acetylcholine receptors.,Luo S, Zhangsun D, Schroeder CI, Zhu X, Hu Y, Wu Y, Weltzin MM, Eberhard S, Kaas Q, Craik DJ, McIntosh JM, Whiteaker P FASEB J. 2014 Jan 7. PMID:24398291 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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