2MTT: Non-reducible analogues of alpha-conotoxin RgIA: [3,12]-cis dicarba RgIA

alpha-Conotoxin RgIA is both an antagonist of the alpha9alpha10 nicotinic acetylcholine receptor (nAChR) subtype and an inhibitor of 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 nonreducible 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.
PDB ID: 2MTTDownload
MMDB ID: 124967
PDB Deposition Date: 2014/8/31
Updated in MMDB: 2014/11
Experimental Method:
solution nmr
Source Organism:
Similar Structures:
Biological Unit for 2MTT: monomeric; determined by author
Molecular Components in 2MTT
Label Count Molecule
Protein (1 molecule)
Dicarba Analogues of Alpha-conotoxin Rgia
Molecule annotation
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