Novel structural insights for a pair of monoclonal antibodies recognizing non-overlapping epitopes of the glucosyltransferase domain of Clostridium difficile toxin B

IF 2.7 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current Research in Structural Biology Pub Date : 2022-01-01 DOI:10.1016/j.crstbi.2022.03.003

Jinyu Liu , Michael Kothe , Jianxin Zhang , Eliud Oloo , Svetlana Stegalkina , Sophia T. Mundle , Lu Li , Jinrong Zhang , Leah E. Cole , Lucianna Barone , Hans-Peter Biemann , Harry Kleanthous , Natalie G. Anosova , Stephen F. Anderson

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Abstract

Clostridium difficile toxins are the primary causative agents for hospital-acquired diarrhea and pseudomembranous colitis. Numerous monoclonal antibodies (mAbs) targeting different domains of Clostridium difficile toxin have been reported. Here we report the crystal structures of two mAbs, B1 and B2, in complex with the glycosyltransferase domain (GTD) of the Clostridium difficile toxin B (TcdB). B2 bound to the N-terminal 4 helix bundle of the GTD, a conserved membrane localization domain (MLD) found in the large clostridial glycosylating toxin family implicated in targeting plasma membrane. B1 bound to a distinct epitope at the hinge region between the MLD and the catalytic subdomain of the GTD. Functional studies revealed the potency of these mAbs in vitro and in vivo to be synergistic when given in combination.

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艰难梭菌毒素B糖基转移酶结构域非重叠表位的一对单克隆抗体的结构新见解

艰难梭菌毒素是医院获得性腹泻和假膜性结肠炎的主要病原体。许多针对艰难梭菌毒素不同结构域的单克隆抗体(mab)已被报道。本文报道了与艰难梭菌毒素B (TcdB)的糖基转移酶结构域(GTD)复合物的两个单克隆抗体B1和B2的晶体结构。B2结合到GTD的n端4螺旋束上，GTD是一个保守的膜定位结构域(MLD)，存在于涉及靶向质膜的大型梭状菌糖基化毒素家族中。B1在MLD和GTD的催化亚域之间的铰链区域结合到一个不同的表位上。功能研究显示，这些单抗在体内和体外的效力在联合给药时具有协同作用。

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