Tan K, Liu J, Wang J, Shen S, Lu M
Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12303-8. doi: 10.1073/pnas.94.23.12303.
Infection by HIV-1 involves the fusion of viral and cellular membranes with subsequent transfer of viral genetic material into the cell. The HIV-1 envelope glycoprotein that mediates fusion consists of the surface subunit gp120 and the transmembrane subunit gp41. gp120 directs virion attachment to the cell-surface receptors, and gp41 then promotes viral-cell membrane fusion. A soluble, alpha-helical, trimeric complex within gp41 composed of N-terminal and C-terminal extraviral segments has been proposed to represent the core of the fusion-active conformation of the HIV-1 envelope. A thermostable subdomain denoted N34(L6)C28 can be formed by the N-34 and C-28 peptides connected by a flexible linker in place of the disulfide-bonded loop region. Three-dimensional structure of N34(L6)C28 reveals that three molecules fold into a six-stranded helical bundle. Three N-terminal helices within the bundle form a central, parallel, trimeric coiled coil, whereas three C-terminal helices pack in the reverse direction into three hydrophobic grooves on the surface of the N-terminal trimer. This thermostable subdomain displays the salient features of the core structure of the isolated gp41 subunit and thus provides a possible target for therapeutics designed selectively to block HIV-1 entry.
HIV-1感染涉及病毒膜与细胞膜的融合，随后病毒遗传物质转移到细胞中。介导融合的HIV-1包膜糖蛋白由表面亚基gp120和跨膜亚基gp41组成。gp120引导病毒体附着于细胞表面受体，然后gp41促进病毒-细胞膜融合。gp41内由N端和C端病毒外区段组成的一种可溶性α-螺旋三聚体复合物被认为代表了HIV-1包膜融合活性构象的核心。通过柔性接头连接N-34和C-28肽代替二硫键连接的环区可形成一个称为N34(L6)C28的热稳定亚结构域。N34(L6)C28的三维结构显示，三个分子折叠成一个六链螺旋束。束内的三个N端螺旋形成一个中心平行三聚体卷曲螺旋，而三个C端螺旋以相反方向堆积到N端三聚体表面的三个疏水凹槽中。这个热稳定亚结构域展示了分离的gp41亚基核心结构的显著特征，因此为选择性阻断HIV-1进入的治疗药物提供了一个可能的靶点。
