Lacy D B, Tepp W, Cohen A C, DasGupta B R, Stevens R C
Department of Chemistry and Earnest Orlando Lawrence Berkeley National Laboratory, University of California, Berkeley, 94720, USA.
Nat Struct Biol. 1998 Oct;5(10):898-902. doi: 10.1038/2338.
Botulinum neurotoxin type A (BoNT/A) is the potent disease agent in botulism, a potential biological weapon and an effective therapeutic drug for involuntary muscle disorders. The crystal structure of the entire 1,285 amino acid di-chain neurotoxin was determined at 3.3 A resolution. The structure reveals that the translocation domain contains a central pair of alpha-helices 105 A long and a approximately 50 residue loop or belt that wraps around the catalytic domain. This belt partially occludes a large channel leading to a buried, negative active site--a feature that calls for radically different inhibitor design strategies from those currently used. The fold of the translocation domain suggests a mechanism of pore formation different from other toxins. Lastly, the toxin appears as a hybrid of varied structural motifs and suggests a modular assembly of functional subunits to yield pathogenesis.
A型肉毒杆菌神经毒素（BoNT/A）是肉毒中毒的致病因子，是一种潜在的生物武器，也是治疗非自主性肌肉疾病的有效治疗药物。完整的1285个氨基酸的双链神经毒素的晶体结构在3.3埃分辨率下得以确定。该结构显示，转位结构域包含一对长达105埃的中央α螺旋以及一个环绕催化结构域的约50个残基的环或带。这条带部分阻塞了一个通向埋藏的负性活性位点的大通道——这一特征要求采用与目前所用方法截然不同的抑制剂设计策略。转位结构域的折叠表明其形成孔道的机制与其他毒素不同。最后，该毒素呈现出多种结构基序的混合体，提示功能性亚基通过模块化组装产生致病作用。
