Structural Investigations on the Interactions between Cytidine Deaminase Human APOBEC3G and DNA
Structural Investigations on the Interactions between Cytidine Deaminase Human APOBEC3G and DNA
复制标题
胞苷脱氨酶人 APOBEC3G 与 DNA 相互作用的结构研究
DOI：
10.1002/asia.201900480
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发表时间：
2019
影响因子：
4.1
通讯作者：
Cao Chunyang
中科院分区：
文献类型：
--
作者：
Yan Xiaoxuan;Lan Wenxian;Wang Chunxi;Cao Chunyang
人APOBEC 3G（A3 G）通过在逆转录过程中使病毒cDNA中靶基序5′-CCC-3′中3′-端的胞苷脱氨基，抑制人免疫缺陷病毒-1的复制。它在体外以3′->5′顺序脱氨两个连续的胞苷。虽然报道了A3 G催化结构域（A3 G-CD 2）与DNA的晶体结构，但尚不清楚参与酶反应的残基为何广泛分布。在DNA 5′-ATTC 4C 5C 6 IA 7ATT-3′（TCCC 6 I）的胞苷（dC 6 I）的C-5位引入碘原子。它将脱氨基序列偏好从CCC切换到TCC，尽管观察到小的dC 6 Ideamination。A3 G-CD 2与产物DNA TCUC 6 I和TCUU 6 I复合物的溶液结构表明底物DNA以TCC和CCC模式结合A3 G-CD 2。dC 6脱氨基与第四碱基类型有关。CCC模式有利于dC 6脱氨基，而TCC模式导致dC 5脱氨基。这些研究为设计抑制剂以阻止病毒进化提供了广泛的基础。
Human APOBEC3G (A3G) inhibits the replication of human immunodeficiency virus‐1 by deaminating cytidine at the 3′‐end in the target motif 5′‐CCC‐3′ in viral cDNA during reverse transcription. It in vitro deaminates two consecutive cytidines in a 3′‐>5′ order. Although a crystal structure of the A3G catalytic domain (A3G‐CD2) with DNA was reported, it is unknown why residues involved in enzymatic reaction are distributed widely. Here, we introduced an iodine atom into the C‐5 position of cytidine (dC6I) in DNA 5′‐ATTC4C5C6IA7ATT‐3′ (TCCC6I). It switches the deamination sequence preference from CCC to TCC, although small dC6Ideamination was observed. Solution structures of A3G‐CD2 in complexes with products DNA TCUC6Iand TCUU6Iindicate that the substrate DNA binds A3G‐CD2 in TCC and CCC modes. The dC6deamination correlates with the 4thbase type. The CCC mode favours dC6deamination, while the TCC mode results in dC5deamination. These studies present an extensive basis to design inhibitors to impede viral evolvability.