Dong X N, Xiao Y, Dierich M P, Chen Y H
Laboratory of Immunology, Department of Biological Science and Technology, Research Centre for Medical Science, Tsinghua University, 100084, Beijing, People's Republic of China.
Immunol Lett. 2001 Jan 15;75(3):215-20. doi: 10.1016/s0165-2478(00)00302-3.
Recent studies demonstrated that the N- and C-domains of HIV-1 gp41 is involved in virus-mediated membrane fusion resulting in HIV-entry into the target cells. Up to now, viral mutation baffled many scientists to develop effective vaccines and drugs against HIV-1. To acquire more information of mutation of gp41 and to reveal the relationship of structure and function of the N- and C-domains, we compared and analyzed amino acid sequences of the gp41 ectodomain (aa 512-681) of 862 isolates from most HIV-1 clades (including A, B, C, D, E, F, G, H, I, J and O clades). A consensus sequence of the ectodomain with the highest frequency emerging on each position is constituted. The fusion domain and the N-domain belong to the most conserved regions in gp41, and most variable residues assemble partial to the C terminal of gp41. The hydrophobicity of each position is also calculated. The a and d positions in the N-domain for maintaining stabilization of the trimeric coiled coil interactions are highly conservative, and the e and g positions in the C-domain to retain the interaction show also highly conservative. The strange high conservation of the c residues may have an implication in the coiled coil structure. The highly conserved residues form the lining of the hydrophobic cavity and the deep cavity is an ideal target for small molecular inhibitors. On the C-terminal of the C-domain there is a highly conserved segment GIVQQQ. They are intimately involved in forming the three interfaces between neighboring helices. The function of the N- and C-domains, such as binding to the potential cellular receptor and inducing protective activities, are also discussed. These studies on the mutation, structure and functions of the N- and C-domains suggested that both domains become a new focus to develop effective vaccine and antiviral drugs in the new strategies.
最近的研究表明，HIV-1 gp41的N结构域和C结构域参与病毒介导的膜融合，从而导致HIV进入靶细胞。到目前为止，病毒突变使许多科学家难以开发针对HIV-1的有效疫苗和药物。为了获取更多关于gp41突变的信息，并揭示N结构域和C结构域的结构与功能关系，我们比较并分析了来自大多数HIV-1进化枝（包括A、B、C、D、E、F、G、H、I、J和O进化枝）的862个分离株的gp41胞外域（氨基酸512 - 681）的氨基酸序列。构建了每个位置出现频率最高的胞外域共有序列。融合结构域和N结构域属于gp41中最保守的区域，大多数可变残基部分聚集在gp41的C末端。还计算了每个位置的疏水性。N结构域中维持三聚体卷曲螺旋相互作用稳定性的a和d位置高度保守，C结构域中保持相互作用的e和g位置也高度保守。c残基奇怪的高度保守可能对卷曲螺旋结构有影响。高度保守的残基形成疏水腔的内衬，而深腔是小分子抑制剂的理想靶点。在C结构域的C末端有一个高度保守的片段GIVQQQ。它们密切参与形成相邻螺旋之间的三个界面。还讨论了N结构域和C结构域的功能，如与潜在细胞受体结合和诱导保护活性。这些关于N结构域和C结构域的突变、结构和功能的研究表明，这两个结构域成为新策略中开发有效疫苗和抗病毒药物的新焦点。
