2MTU

Non-reducible analogues of alpha-conotoxin RgIA: [3,12]-trans dicarba RgIA

2MTU の概要

• エントリーDOI: 10.2210/pdb2mtu/pdb
• 関連するPDBエントリー: 2MTU
• NMR情報: BMRB: 25187
• 分子名称: Dicarba Analogues of alpha-Conotoxin RgIA (1 entity in total)
• 機能のキーワード: dicarba, rgia, alpha-conotoxin, non-reducible, de novo protein
• 由来する生物種: synthetic construct
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 1542.79

構造登録者

Chhabra, S.,Robinson, S.D.,Norton, R.S. (登録日: 2014-09-01, 公開日: 2014-11-26, 最終更新日: 2023-12-27)

主引用文献

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

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: 25393758
DOI: 10.1021/jm501126u

実験手法

SOLUTION NMR