6KN2

Structure of single disulfide peptide Czon1107-WT (major conformer)

6KN2 の概要

• エントリーDOI: 10.2210/pdb6kn2/pdb
• NMR情報: BMRB: 36275
• 分子名称: Czon1107-WT (Conformer A) (1 entity in total)
• 機能のキーワード: nachr anatgonist nmr, neuropeptide
• 由来する生物種: Conus zonatus
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 1109.32

構造登録者

Sarma, S.P.,Madhan Kumar, M. (登録日: 2019-08-02, 公開日: 2020-04-08, 最終更新日: 2024-10-23)

主引用文献

Mohan, M.K.,Abraham, N.,R P, R.,Jayaseelan, B.F.,Ragnarsson, L.,Lewis, R.J.,Sarma, S.P.
Structure and allosteric activity of a single-disulfide conopeptide fromConus zonatusat human alpha 3 beta 4 and alpha 7 nicotinic acetylcholine receptors.
J.Biol.Chem., 295:7096-7112, 2020

PubMed Abstract: Conopeptides are neurotoxic peptides in the venom of marine cone snails and have broad therapeutic potential for managing pain and other conditions. Here, we identified the single-disulfide peptides Czon1107 and Cca1669 from the venoms of and , respectively. We observed that Czon1107 strongly inhibits the human α3β4 (IC 15.7 ± 3.0 μm) and α7 (IC 77.1 ± 0.05 μm) nicotinic acetylcholine receptor (nAChR) subtypes, but the activity of Cca1669 remains to be identified. Czon1107 acted at a site distinct from the orthosteric receptor site. Solution NMR experiments revealed that Czon1107 exists in equilibrium between conformational states that are the result of a key Ser-Pro isomerization. Moreover, we found that the X-Pro amide bonds in the inter-cysteine loop are rigidly constrained to conformations. Structure-activity experiments of Czon1107 and its variants at positions P5 and P7 revealed that the conformation around the X-Pro bonds () plays an important role in receptor subtype selectivity. The conformation at the Cys-Pro peptide bond was essential for α3β4 nAChR subtype allosteric selectivity. In summary, we have identified a unique single-disulfide conopeptide with a noncompetitive, potentially allosteric inhibitory mechanism at the nAChRs. The small size and rigidity of the Czon1107 peptide could provide a scaffold for rational drug design strategies for allosteric nAChR modulation. This new paradigm in the "conotoxinomic" structure-function space provides an impetus to screen venom from other species for similar, short bioactive peptides that allosterically modulate ligand-gated receptor function.

PubMed: 32234761
DOI: 10.1074/jbc.RA119.012098

実験手法

SOLUTION NMR