Lugo Miguel R, Merrill A Rod
Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, N1G 2W1, Canada.
J Mol Recognit. 2015 Sep;28(9):539-52. doi: 10.1002/jmr.2469. Epub 2015 Mar 9.
Cholix toxin from Vibrio cholerae is a novel mono-ADP-ribosyltransferase (mART) toxin that shares structural and functional properties with Pseudomonas aeruginosa exotoxin A and Corynebacterium diphtheriae diphtheria toxin. Herein, we have used the high-resolution X-ray structure of full-length cholix toxin in the apo form, NAD(+) bound, and 10 structures of the cholix catalytic domain (C-domain) complexed with several strong inhibitors of toxin enzyme activity (NAP, PJ34, and the P-series) to study the binding mode of the ligands. A pharmacophore model based on the active pose of NAD(+) was compared with the active conformation of the inhibitors, which revealed a cationic feature in the side chain of the inhibitors that may determine the active pose. Moreover, a conformational search was conducted for the missing coordinates of one of the main active-site loops (R-loop). The resulting structural models were used to evaluate the interaction energies and for 3D-QSAR modeling. Implications for a rational drug design approach for mART toxins were derived.
霍乱弧菌的Cholix毒素是一种新型单ADP核糖基转移酶（mART）毒素，与铜绿假单胞菌外毒素A和白喉棒状杆菌白喉毒素具有结构和功能特性。在此，我们利用全长Cholix毒素在无配体形式、结合NAD(+)以及与几种强力毒素酶活性抑制剂（NAP、PJ34和P系列）复合的Cholix催化结构域（C结构域）的10种结构，研究配体的结合模式。将基于NAD(+)活性构象的药效团模型与抑制剂的活性构象进行比较，结果显示抑制剂侧链具有阳离子特征，这可能决定其活性构象。此外，对一个主要活性位点环（R环）缺失的坐标进行了构象搜索。所得结构模型用于评估相互作用能并进行三维定量构效关系建模。由此得出了针对mART毒素的合理药物设计方法的相关启示。
