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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Crystal structure of Clostridium botulinum neurotoxin protease in a product-bound state: Evidence for noncanonical zinc protease activity.
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Crystal structure of Clostridium botulinum neurotoxin protease in a product-bound state: Evidence for noncanonical zinc protease activity.

机译：产物结合状态下的肉毒梭菌神经毒素蛋白酶的晶体结构：非规范锌蛋白酶活性的证据。

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摘要

Clostridium botulinum neurotoxins (BoNTs), the most potent toxins known, disrupt neurotransmission through proteolysis of proteins involved in neuroexocytosis. The light chains of BoNTs are unique zinc proteases that have stringent substrate specificity and require exceptionally long substrates. We have determined the crystal structure of the protease domain from BoNT serotype A (BoNT/A). The structure reveals a homodimer in a product-bound state, with loop F242-V257 from each monomer deeply buried in its partner's catalytic site. The loop, which acts as a substrate, is oriented in reverse of the canonical direction for other zinc proteases. The Y249-Y250 peptide bond of the substrate loop is hydrolyzed, leaving the Y249 product carboxylate coordinated to the catalytic zinc. From the crystal structure of the BoNT/A protease, detailed models of noncanonical binding and proteolysis can be derived which we propose are also consistent with BoNT/A binding and proteolysis of natural substrate synaptosome-associated protein of 25 kDa (SNAP-25). The proposed BoNT/A substrate-binding mode and catalytic mechanism are markedly different from those previously proposed for the BoNT serotype B.
机译：肉毒梭菌神经毒素（BoNT）是已知最有效的毒素，它通过蛋白水解涉及神经胞吐作用的蛋白质来破坏神经传递。 BoNT的轻链是独特的锌蛋白酶，具有严格的底物特异性，并且需要极长的底物。我们已经确定了来自BoNT血清型A（BoNT / A）的蛋白酶域的晶体结构。该结构揭示了一个同质二聚体处于产物结合状态，每个单体的环F242-V257深深地埋在其伴侣的催化位点中。用作底物的环的方向与其他锌蛋白酶的标准方向相反。底物环的Y249-Y250肽键被水解，使Y249产物的羧酸盐与催化锌配位。从BoNT / A蛋白酶的晶体结构中，可以得出详细的非规范结合和蛋白水解模型，我们提出的模型也与25kDa的天然底物突触体相关蛋白（SNAP-25）的BoNT / A结合和蛋白水解相一致。所提出的BoNT / A底物结合模式和催化机理与先前针对BoNT血清型B提出的那些显着不同。

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