Mutations of an antibody binding energy hot spot on domain III of the dengue 2 envelope glycoprotein exploited for neutralization escape
Mutations of an antibody binding energy hot spot on domain III of the dengue 2 envelope glycoprotein exploited for neutralization escape
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DOI：
10.1016/j.virol.2010.06.044
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发表时间：
2010-11-25
期刊：
影响因子：
3.7
通讯作者：
Barrett, Alan D. T.
中科院分区：
文献类型：
--
作者：
Gromowski, Gregory D.;Roehrig, John T.;Barrett, Alan D. T.
先前的晶体学研究已经鉴定了总共11个DENV-2包膜蛋白结构域III（ED 3）残基（K305、F306、K307、V308、V309、K310、I312、Q325、P364、K388和N390），其通过侧链和主链接触相互作用，用登革病毒（DENV）亚复合体特异性中和单克隆抗体（MAb）1A 1D-2的Fab（Lok等，2008年）。在此，我们使用DENV-2重组ED 3突变体的MAb 1A 1D-2结构表位残基来确定该MAb的功能表位。残基K307、K310和I312的侧链被确定为对于MAb结合是功能关键的，并且因此构成MAb 1A 1D-2在DENV-2 ED 3上的结合能的热点。总体而言，这些发现表明，MAb 1A 1D-2的结构表位内的氨基酸残基侧链的仅一个子集定义了DENV-2 ED 3上的功能表位，其对于MAb结合和中和逃逸是必需的。(C)2010年由Elsevier Inc.出版
Previous crystallographic studies have identified a total of 11 DENV-2 envelope protein domain III (ED3) residues (K305, F306, K307, V308, V309, K310, I312, Q325, P364, K388, and N390) that interacted, through both side- and main-chain contacts, with the Fab of a dengue virus (DENV) subcomplex-specific neutralizing monoclonal antibody (MAb) 1A1D-2 (Lok et al., 2008). Here, we used DENV-2 recombinant ED3 mutants of the MAb 1A1D-2 structural epitope residues to determine the functional epitope of this MAb. The side-chains of residues K307, K310 and I312 were determined to be functionally critical for MAb binding, and thus constitute a hot spot of binding energy for MAb 1A1D-2 on the DENV-2 ED3. Overall, these findings demonstrate that only a subset of the amino acid residue side-chains within the structural epitope of MAb 1A1D-2 define a functional epitope on the DENV-2 ED3 that is essential for MAb binding and neutralization escape. (C) 2010 Published by Elsevier Inc.