9BAF

Solution NMR structure of conofurin-Delta

9BAF の概要

• エントリーDOI: 10.2210/pdb9baf/pdb
• NMR情報: BMRB: 31156
• 分子名称: Alpha-conotoxin LvIA (1 entity in total)
• 機能のキーワード: conotoxin, nicotinic acetylcholine receptor, neuropeptide
• 由来する生物種: Conus lividus
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 1753.07

構造登録者

Harvey, P.J.,Craik, D.J.,Hone, A.J.,McIntosh, J.M. (登録日: 2024-04-04, 公開日: 2024-07-03, 最終更新日: 2024-10-16)

主引用文献

Hone, A.J.,Santiago, U.,Harvey, P.J.,Tekarli, B.,Gajewiak, J.,Craik, D.J.,Camacho, C.J.,McIntosh, J.M.
Design, Synthesis, and Structure-Activity Relationships of Novel Peptide Derivatives of the Severe Acute Respiratory Syndrome-Coronavirus-2 Spike-Protein that Potently Inhibit Nicotinic Acetylcholine Receptors.
J.Med.Chem., 67:9587-9598, 2024

PubMed Abstract: The spike-protein of SARS-CoV-2 has a distinctive amino-acid sequence (RRARS) that forms a cleavage site for the enzyme furin. Strikingly, the structure of the spike-protein loop containing the furin cleavage site bears substantial similarity to neurotoxin peptides found in the venoms of certain snakes and marine cone snails. Leveraging this relationship, we designed and synthesized disulfide-constrained peptides with amino-acid sequences corresponding to the furin cleavage-sites of wild-type (B.1 variant) SARS-CoV-2 or the Alpha, Delta, and Omicron variants. Remarkably, some of these peptides potently inhibited α7 and α9α10 nicotinic acetylcholine receptors (nAChR) with nM affinity and showed SARS-CoV-2 variant and nAChR subtype-dependent potencies. Nuclear magnetic resonance spectroscopy and molecular dynamics were used to rationalize structure-activity relationships between peptides and their cognate receptors. These findings delineate nAChR subtypes that can serve as high-affinity spike-protein targets in tissues central to COVID-19 pathophysiology and identify ligands and target receptors to inform the development of novel SARS-CoV-2 therapeutics.

PubMed: 38814877
DOI: 10.1021/acs.jmedchem.4c00735

実験手法

SOLUTION NMR