3DSE

A potent peptidomimetic inhibitor of botulinum neurotoxin serotype A has a very different conformation than SNAP-25 substrate

3DSE の概要

• エントリーDOI: 10.2210/pdb3dse/pdb
• 関連するPDBエントリー: 1XTF 2ISG 3DS9 3DSE
• 分子名称: Botulinum neurotoxin type A, ZINC ION, NICKEL (II) ION, ... (4 entities in total)
• 機能のキーワード: snare, botulism, inhibition, metalloprotease, neurotransmission, neuromuscular junction, hydrolase, membrane, metal-binding, neurotoxin, pharmaceutical, protease, secreted, toxin, transmembrane, zinc
• 由来する生物種: Clostridium botulinum
• 細胞内の位置: Botulinum neurotoxin A light chain: Secreted. Botulinum neurotoxin A heavy chain: Secreted: A5HZZ9
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 47902.09

構造登録者

Zuniga, J.E.,Fenn, T. (登録日: 2008-07-11, 公開日: 2008-09-30, 最終更新日: 2024-02-21)

主引用文献

Zuniga, J.E.,Schmidt, J.J.,Fenn, T.,Burnett, J.C.,Arac, D.,Gussio, R.,Stafford, R.G.,Badie, S.S.,Bavari, S.,Brunger, A.T.
A Potent Peptidomimetic Inhibitor of Botulinum Neurotoxin Serotype A Has a Very Different Conformation than SNAP-25 Substrate
Structure, 16:1588-1597, 2008

PubMed Abstract: Botulinum neurotoxin serotype A is the most lethal of all known toxins. Here, we report the crystal structure, along with SAR data, of the zinc metalloprotease domain of BoNT/A bound to a potent peptidomimetic inhibitor (K(i)=41 nM) that resembles the local sequence of the SNAP-25 substrate. Surprisingly, the inhibitor adopts a helical conformation around the cleavage site, in contrast to the extended conformation of the native substrate. The backbone of the inhibitor's P1 residue displaces the putative catalytic water molecule and concomitantly interacts with the "proton shuttle" E224. This mechanism of inhibition is aided by residue contacts in the conserved S1' pocket of the substrate binding cleft and by the induction of new hydrophobic pockets, which are not present in the apo form, especially for the P2' residue of the inhibitor. Our inhibitor is specific for BoNT/A as it does not inhibit other BoNT serotypes or thermolysin.

PubMed: 18940613
DOI: 10.1016/j.str.2008.07.011

実験手法

X-RAY DIFFRACTION (1.9 Å)