Nature:人体天生抗HIV能力得以阐明

发布者：科学网 发布时间：2008-10-20　

人类具有内置的抗HIV的武器——名为APOBEC-3G的酶，但迄今无人知道该如何开启它的潜能。美国科学家近日研究揭示了这种酶的原子结构，为药物开发指明了新方向。相关论文10月12日在线发表于《自然》（Nature）杂志上。

APOBEC-3G存在于每个人类细胞中，它能从一开始就阻止HIV的复制，即RNA向DNA的转录。在最新的研究中，美国南加州大学的Xiaojiang Chen和同事揭示了APOBEC-3G活性部分的原子结构，这一结构说明了APOBEC-3G如何绑定到病毒DNA的特殊位点，令其发生突变并将其破坏。Chen说：“我们弄清了这个酶如何与DNA相互作用，这为设计抗HIV药物提供了平台。”

然而，既然有APOBEC-3G的存在，为什么人类还会患上艾滋病？因为HIV的进化编码了蛋白Vif（毒性因子），抑制了APOBEC-3G，这样它就能成功地进行转录，形成感染并制造更多的病毒。

Chen说，他们的研究对于Vif绑定到APOBEC-3G的位点提供了重要的线索。这可被用于设计药物阻止Vif的绑定，使APOBEC-3G能够发挥作用。这将开启人类先天的抗HIV能力，他说：“我们生而具有这一武器，它一直等着被开启。”

除了抵抗HIV之外，APOBEC-3G还能抑制乙肝病毒。APOBEC家族的其它成员在抗体成熟、脂肪代谢和心脏发育方面发挥着重要作用。Chen表示，在原子水平描绘APOBEC-3G结构的目标“因其重要性而一直被全世界科学家所追求”。

Nature advance online publication 12 October 2008 | doi:10.1038/nature07357; Received 3 June 2008; Accepted 13 August 2008; Published online 12 October 2008

Crystal structure of the anti-viral APOBEC3G catalytic domain and functional implications

Lauren G. Holden1,3, Courtney Prochnow1,3, Y. Paul Chang1,3, Ronda Bransteitter1, Linda Chelico1, Udayaditya Sen1, Raymond C. Stevens2, Myron F. Goodman1 & Xiaojiang S. Chen1

1. Molecular and Computational Biology, University of Southern California, Los Angeles, California 90089, USA
2. Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
3. These authors contributed equally to this work.

Correspondence to: Xiaojiang S. Chen1 Correspondence and requests for materials should be addressed to X.S.C. (Email: xiaojiang.chen@usc.edu).

The APOBEC family members are involved in diverse biological functions. APOBEC3G restricts the replication of human immunodeficiency virus (HIV), hepatitis B virus and retroelements by cytidine deamination on single-stranded DNA or by RNA binding1, 2, 3, 4. Here we report the high-resolution crystal structure of the carboxy-terminal deaminase domain of APOBEC3G (APOBEC3G-CD2) purified from Escherichia coli. The APOBEC3G-CD2 structure has a five-stranded -sheet core that is common to all known deaminase structures and closely resembles the structure of another APOBEC protein, APOBEC2 (ref. 5). A comparison of APOBEC3G-CD2 with other deaminase structures shows a structural conservation of the active-site loops that are directly involved in substrate binding. In the X-ray structure, these APOBEC3G active-site loops form a continuous 'substrate groove' around the active centre. The orientation of this putative substrate groove differs markedly (by 90 degrees) from the groove predicted by the NMR structure6. We have introduced mutations around the groove, and have identified residues involved in substrate specificity, single-stranded DNA binding and deaminase activity. These results provide a basis for understanding the underlying mechanisms of substrate specificity for the APOBEC family.