Crystal structure of the engineered neutralizing antibody M18 complexed to domain 4 of the anthrax protective antigen.
Crystal structure of the engineered neutralizing antibody M18 complexed to domain 4 of the anthrax protective antigen.
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DOI：
10.1016/j.jmb.2009.02.003
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发表时间：
2009-04-03
影响因子：
5.6
通讯作者：
Robertus, Jon D.
中科院分区：
文献类型：
--
作者：
Leysath, Clinton E.;Monzingo, Arthur F.;Maynard, Jennifer A.;Barnett, Jason;Georgiou, George;Iverson, Brent L.;Robertus, Jon D.
炭疽芽孢杆菌的毒力与炭疽毒素的细胞毒性成分、致死因子(LF)和水肿因子(EF)密切相关。LF和EF通过与保护性抗原(PA)相互作用进入宿主细胞，PA与宿主细胞受体如CMG2结合。中和PA的抗体已被证明在动物模型中具有保护作用，并正在进行紧张的临床开发。据报道，鼠源性单抗14B7可与PA(PAD4)的结构域4相互作用，并阻断其与CMG2的结合。最近，14B7抗体被用作筛选非常高亲和力的单链抗体的平台，这种抗体具有巨大的潜力，可以作为炭疽预防和治疗的组合。在这里，我们报告了14B7家族中三个高亲和力单链抗体：14B7和两个高亲和力变异体1H和M18的高分辨X射线结构。此外，我们还提出了第一个中和抗体-PA结构，M18与PAD4的络合物，分辨率为3.8？这些结构提供了对中和机制和各种突变对抗体亲和力的影响的洞察，并能够比较M18抗体和CMG2与PAD4的结合。
The virulence of Bacillus anthracis is critically dependent on the cytotoxic components of the anthrax toxin, lethal factor (LF) and edema factor (EF). LF and EF gain entry into host cells through interactions with the protective antigen (PA), which binds to host cellular receptors such as CMG2. Antibodies that neutralize PA have been shown to confer protection in animal models and are undergoing intense clinical development. A murine monoclonal antibody, 14B7, has been reported to interact with domain 4 of PA (PAD4) and block its binding to CMG2. More recently, the 14B7 antibody was used as the platform for the selection of very high affinity single chain antibodies that have tremendous potential as a combination anthrax prophylactic and treatment. Here we report the high resolution X-ray structures of three high affinity single chain antibodies in the 14B7 family; 14B7 and two high affinity variants 1H and M18. In addition, we present the first neutralizing antibody-PA structure, M18 in complex with PAD4 at 3.8 Å resolution. These structures provide insights into the mechanism of neutralization and on the effect of various mutations on antibody affinity and enable a comparison between the binding of the M18 antibody and CMG2 with PAD4.
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DOI：
10.1107/s0907444901012458
发表时间：
2001-10-01
影响因子：
2.2
作者：
Kissinger, CR;Gehlhaar, DK;Bouzida, D
通讯作者：
Bouzida, D
影响因子：
56.9
作者：
AMIT, AG;MARIUZZA, RA;POLJAK, RJ
通讯作者：
POLJAK, RJ
影响因子：
2.7
作者：
Braden, BC;Fields, BA;Poljak, RJ
通讯作者：
Poljak, RJ
影响因子：
3.1
作者：
Kobiler, D;Gozes, Y;Altboum, Z
通讯作者：
Altboum, Z
影响因子：
14.9
作者：
Davis IW;Leaver-Fay A;Chen VB;Block JN;Kapral GJ;Wang X;Murray LW;Arendall WB 3rd;Snoeyink J;Richardson JS;Richardson DC
通讯作者：
Richardson DC