2MTO
Non-reducible analogues of alpha-conotoxin RgIA: [2,8]-cis dicarba RgIA
Summary for 2MTO
| Entry DOI | 10.2210/pdb2mto/pdb |
| Related | 2JUT |
| NMR Information | BMRB: 25174 |
| Descriptor | Alpha-conotoxin RgIA (1 entity in total) |
| Functional Keywords | dicarba, rgia, non-reducible, toxin |
| Biological source | Conus regius (Crown cone) |
| Cellular location | Secreted : P0C1D0 |
| Total number of polymer chains | 1 |
| Total formula weight | 1542.79 |
| Authors | Chhabra, S.,Robinson, S.,Norton, R. (deposition date: 2014-08-26, release date: 2014-11-26, Last modification date: 2023-06-14) |
| Primary citation | Chhabra, S.,Belgi, A.,Bartels, P.,van Lierop, B.J.,Robinson, S.D.,Kompella, S.N.,Hung, A.,Callaghan, B.P.,Adams, D.J.,Robinson, A.J.,Norton, R.S. Dicarba Analogues of alpha-Conotoxin RgIA. Structure, Stability, and Activity at Potential Pain Targets. J.Med.Chem., 57:9933-9944, 2014 Cited by PubMed Abstract: α-Conotoxin RgIA is both an antagonist of the α9α10 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 α9α10 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. PubMed: 25393758DOI: 10.1021/jm501126u PDB entries with the same primary citation |
| Experimental method | SOLUTION NMR |
Structure validation
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