2mto | pdb_00002mto

Non-reducible analogues of alpha-conotoxin RgIA: [2,8]-cis dicarba RgIA

spinqualitylabelsall models 2mto, 20 NMR models Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2mto is a 1 chain structure. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. NonStd Res: ABA Related: 2jut Resources: FirstGlance, OCA, RCSB, PDBsum Function [CXA1A_CONRE] Alpha-conotoxins act on postsynaptic membranes, they bind to the nicotinic acetylcholine receptors (nAChR) and thus inhibit them. Is a specific blocker of the alpha-9/alpha-10 nAChR. Is also active on alpha-7 (but 1000-fold less potent) and on alpha-2/beta-2, alpha-2/beta-4, alpha-3/beta-4, alpha-3/beta-2, alpha-4/beta-2, alpha-4/beta-4 and alpha-6 or -3/beta-2 or -3 (but 2000-fold less potent) channels. Publication Abstract from PubMed alpha-Conotoxin RgIA is an antagonist of the alpha9alpha10 nicotinic acetylcholine receptor (nAChR) subtype and also inhibits high voltage-activated N-type calcium channel currents. RgIA has therapeutic potential for the treatment of pain but reduction of the disulfide bond framework under physiological conditions represents a potential liability for clinical applications. We synthesized four RgIA analogues that replaced native disulfide pairs with non-reducible dicarba bridges. Solution structures were determined by NMR, activity assessed against biological targets and stability evaluated in human serum. [3,12]-dicarba analogues retained inhibition of ACh-evoked currents at alpha9alpha10 nAChRs but not N-type calcium channel currents, whereas [2,8]-dicarba analogues displayed the opposite pattern of selectivity. The [2,8] dicarba RgIA analogues were effective in HEK293 cells stably expressing human Cav2.2 channels and transfected with human GABAB receptors. The analogues also exhibited improved serum stability over the native peptide. These selectively acting dicarba analogues may represent mechanistic probes to explore analgesia-related biological receptors. Dicarba Analogues of alpha-Conotoxin RgIA. Structure, Stability and Activity at Potential Pain Targets.,Chhabra S, Belgi A, Bartels P, Vanlierop BJ, Robinson SD, Kompella SN, Hung A, Callaghan BP, Adams DJ, Robinson AJ, Norton RS J Med Chem. 2014 Nov 13. PMID:25393758 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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