Lu M, Ji H, Shen S
Department of Biochemistry, Weill Medical College of Cornell University, New York, New York 10021, USA.
J Virol. 1999 May;73(5):4433-8. doi: 10.1128/JVI.73.5.4433-4438.1999.
The envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1) consists of two subunits, gp120 and gp41. The extraviral portion (ectodomain) of gp41 contains an alpha-helical domain that likely represents the core of the fusion-active conformation of the molecule. Here we report the identification and characterization of a minimal, autonomous folding subdomain that retains key determinants in specifying the overall fold of the gp41 ectodomain core. This subdomain, designated N34(L6)C28, is formed by covalent attachment of peptides N-34 and C-28 by a short flexible linker in place of the normal disulfide-bonded loop sequence. N34(L6)C28 forms a highly thermostable, alpha-helical trimer. Point mutations within the envelope protein complex that abolish membrane fusion and HIV-1 infectivity also impede the formation of the N34(L6)C28 core. Moreover, N34(L6)C28 is capable of inhibiting HIV-1 envelope-mediated membrane fusion. Taken together, these results indicate that the N34(L6)C28 core plays a direct role in the membrane fusion step of HIV-1 infection and thus provides a molecular target for the development of antiviral pharmaceutical agents.
人类免疫缺陷病毒1型（HIV-1）的包膜糖蛋白由两个亚基gp120和gp41组成。gp41的病毒外部分（胞外域）包含一个α螺旋结构域，该结构域可能代表了分子融合活性构象的核心。在此，我们报告了一个最小的、自主折叠亚结构域的鉴定和表征，该亚结构域在确定gp41胞外域核心的整体折叠中保留了关键决定因素。这个亚结构域被命名为N34(L6)C28，它是由肽段N-34和C-28通过一个短的柔性接头共价连接形成的，取代了正常的二硫键连接环序列。N34(L6)C28形成了一个高度耐热的α螺旋三聚体。包膜蛋白复合物中那些消除膜融合和HIV-1感染性的点突变也会阻碍N34(L6)C28核心的形成。此外，N34(L6)C28能够抑制HIV-1包膜介导的膜融合。综上所述，这些结果表明N34(L6)C28核心在HIV-1感染的膜融合步骤中起直接作用，因此为抗病毒药物的开发提供了一个分子靶点。
