4Z7P

X-ray structure of racemic ShK Q16K toxin

4Z7P の概要

• エントリーDOI: 10.2210/pdb4z7p/pdb
• 関連するPDBエントリー: 4LFS
• 分子名称: Potassium channel toxin kappa-stichotoxin-She1a, SULFATE ION (3 entities in total)
• 機能のキーワード: shk toxin, toxin
• 由来する生物種: Stoichactis helianthus (Carribean sea anemone)
• 細胞内の位置: Secreted: P29187
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 4551.26

構造登録者

Sickmier, E.A. (登録日: 2015-04-07, 公開日: 2015-09-09, 最終更新日: 2024-11-06)

主引用文献

Murray, J.K.,Qian, Y.X.,Liu, B.,Elliott, R.,Aral, J.,Park, C.,Zhang, X.,Stenkilsson, M.,Salyers, K.,Rose, M.,Li, H.,Yu, S.,Andrews, K.L.,Colombero, A.,Werner, J.,Gaida, K.,Sickmier, E.A.,Miu, P.,Itano, A.,McGivern, J.,Gegg, C.V.,Sullivan, J.K.,Miranda, L.P.
Pharmaceutical Optimization of Peptide Toxins for Ion Channel Targets: Potent, Selective, and Long-Lived Antagonists of Kv1.3.
J.Med.Chem., 58:6784-6802, 2015

PubMed Abstract: To realize the medicinal potential of peptide toxins, naturally occurring disulfide-rich peptides, as ion channel antagonists, more efficient pharmaceutical optimization technologies must be developed. Here, we show that the therapeutic properties of multiple cysteine toxin peptides can be rapidly and substantially improved by combining direct chemical strategies with high-throughput electrophysiology. We applied whole-molecule, brute-force, structure-activity analoging to ShK, a peptide toxin from the sea anemone Stichodactyla helianthus that inhibits the voltage-gated potassium ion channel Kv1.3, to effectively discover critical structural changes for 15× selectivity against the closely related neuronal ion channel Kv1.1. Subsequent site-specific polymer conjugation resulted in an exquisitely selective Kv1.3 antagonist (>1000× over Kv1.1) with picomolar functional activity in whole blood and a pharmacokinetic profile suitable for weekly administration in primates. The pharmacological potential of the optimized toxin peptide was demonstrated by potent and sustained inhibition of cytokine secretion from T cells, a therapeutic target for autoimmune diseases, in cynomolgus monkeys.

PubMed: 26288216
DOI: 10.1021/acs.jmedchem.5b00495

実験手法

X-RAY DIFFRACTION (1.2 Å)