Paring Down HIV Env: Design and Crystal Structure of a Stabilized Inner Domain of HIV-1 gp120 Displaying a Major ADCC Target of the A32 Region.
Paring Down HIV Env: Design and Crystal Structure of a Stabilized Inner Domain of HIV-1 gp120 Displaying a Major ADCC Target of the A32 Region.
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DOI：
10.1016/j.str.2016.03.005
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发表时间：
2016-05-03
期刊：
影响因子：
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通讯作者：
Pazgier M
中科院分区：
文献类型：
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作者：
Tolbert WD;Gohain N;Veillette M;Chapleau JP;Orlandi C;Visciano ML;Ebadi M;DeVico AL;Fouts TR;Finzi A;Lewis GK;Pazgier M
证据支持抗体依赖性细胞毒性（ADCC）对gp 120的第一和第二恒定（C1-C2）区中的过渡表位（A32样表位）在预防HIV-1感染和疫苗诱导的保护中的作用。在这里，我们描述了第一次成功的尝试，在隔离的内部结构域（ID）的gp 120作为一个独立的分子，封装的A32样区域内的HIV-1的包膜的最小结构单元。通过基于结构的设计，我们开发了ID 2，它由独立于外部结构域表达的ID组成，并通过层间二硫键稳定在CD 4结合构象中。ID 2在CD 4触发的全长gp 120的背景下表达C1-C2表位，但不存在任何已知的中和表位。因此，ID 2代表用于分析和/或选择性诱导针对A32表位区的抗体应答的新探针。我们还提出了ID 2与mAb A32复合的晶体结构，其定义了其表位。ID 2由独立于外部结构域表达的gp 120内部结构域组成ID 2在HIV-1的最小结构单元内展示A32 ADCC表位Env ID 2通过层间二硫键稳定在CD 4结合构象中A32表位映射到gp 120的C1-C2区的第1层和第2层Tolbert等人描述了一种新的构建体ID 2，由独立于外结构域表达的gp 120的内结构域组成。ID 2在HIV-1 Env的最小结构单元内表达A32 ADCC表位，因此它是分析和/或选择性诱导A32样抗体反应的新型探针。
Evidence supports a role of antibody-dependent cellular cytotoxicity (ADCC) toward transitional epitopes in the first and second constant (C1-C2) regions of gp120 (A32-like epitopes) in preventing HIV-1 infection and in vaccine-induced protection. Here, we describe the first successful attempt at isolating the inner domain (ID) of gp120 as an independent molecule that encapsulates the A32-like region within a minimal structural unit of the HIV-1 Env. Through structure-based design, we developed ID2, which consists of the ID expressed independently of the outer domain and stabilized in the CD4-bound conformation by an inter-layer disulfide bond. ID2 expresses C1-C2 epitopes in the context of CD4-triggered full-length gp120 but without any known neutralizing epitope present. Thus, ID2 represents a novel probe for the analysis and/or selective induction of antibody responses to the A32 epitope region. We also present the crystal structure of ID2 complexed with mAb A32, which defines its epitope. ID2 consists of the gp120 inner domain expressed independently of the outer domain ID2 displays the A32 ADCC epitope within minimal structural unit of the HIV-1 Env ID2 is stabilized in the CD4-bound conformation by an inter-layer disulfide bond The A32 epitope maps to layers 1 and 2 of the C1-C2 region of gp120 Tolbert at al. describe a novel construct, ID2, consisting of inner domain of gp120 expressed independently of outer domain. ID2 expresses the A32 ADCC epitope within a minimal structural unit of the HIV-1 Env, thus it is a novel probe for the analysis and/or selective induction of A32-like antibody responses.