4ELC
Crystal structure of the catalytic domain of botulinum neurotoxin BoNT/A C134 mutant with MTSEA modified Cys-165
4ELC の概要
エントリーDOI | 10.2210/pdb4elc/pdb |
関連するPDBエントリー | 2ISE 3BWI 4EJ5 4EL4 |
分子名称 | Botulinum neurotoxin A light chain, ZINC ION, IMIDAZOLE, ... (9 entities in total) |
機能のキーワード | metalloprotease, peptidase m27 superfamily, clostridial neurotoxin zinc protease, human target snap-25, hydrolase |
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: P10845 |
タンパク質・核酸の鎖数 | 1 |
化学式量合計 | 51985.81 |
構造登録者 | Stura, E.A.,Vera, L.,Ptchelkine, D.,Bakirci, H.,Garcia, S.,Dive, V. (登録日: 2012-04-10, 公開日: 2012-08-15, 最終更新日: 2023-09-20) |
主引用文献 | Stura, E.A.,Le Roux, L.,Guitot, K.,Garcia, S.,Bregant, S.,Beau, F.,Vera, L.,Collet, G.,Ptchelkine, D.,Bakirci, H.,Dive, V. Structural Framework for Covalent Inhibition of Clostridium botulinum Neurotoxin A by Targeting Cys165. J.Biol.Chem., 287:33607-33614, 2012 Cited by PubMed Abstract: Clostridium botulinum neurotoxin type A (BoNT/A) is one of the most potent toxins for humans and a major biothreat agent. Despite intense chemical efforts over the past 10 years to develop inhibitors of its catalytic domain (catBoNT/A), highly potent and selective inhibitors are still lacking. Recently, small inhibitors were reported to covalently modify catBoNT/A by targeting Cys(165), a residue located in the enzyme active site just above the catalytic zinc ion. However, no direct proof of Cys(165) modification was reported, and the poor accessibility of this residue in the x-ray structure of catBoNT/A raises concerns about this proposal. To clarify this issue, the functional role of Cys(165) was first assessed through a combination of site-directed mutagenesis and structural studies. These data suggested that Cys(165) is more involved in enzyme catalysis rather than in structural property. Then by peptide mass fingerprinting and x-ray crystallography, we demonstrated that a small compound containing a sulfonyl group acts as inhibitor of catBoNT/A through covalent modification of Cys(165). The crystal structure of this covalent complex offers a structural framework for developing more potent covalent inhibitors catBoNT/A. Other zinc metalloproteases can be founded in the protein database with a cysteine at a similar location, some expressed by major human pathogens; thus this work should find broader applications for developing covalent inhibitors. PubMed: 22869371DOI: 10.1074/jbc.M112.396697 主引用文献が同じPDBエントリー |
実験手法 | X-RAY DIFFRACTION (1.8 Å) |
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