Structure of the membrane proximal external region of HIV-1 envelope glycoprotein
Structure of the membrane proximal external region of HIV-1 envelope glycoprotein
复制标题
DOI：
10.1073/pnas.1807259115
复制
发表时间：
2018-09-18
影响因子：
11.1
通讯作者：
Chou, James J.
中科院分区：
文献类型：
--
作者：
Fu, Qingshan;Shaik, Md Munan;Chou, James J.
HIV-1包膜糖蛋白(Env)的膜近端外区(MPER)含有来自感染者的广谱中和抗体(BNAbs)表位，因此它是一个潜在的疫苗靶点。我们报道了MPER及其相邻跨膜结构域的核磁共振结构，该结构类似于脂质双层膜。MPER很大程度上位于脂质双层之外。它折叠成一个三重簇，主要由保守的疏水残基稳定，并可能通过与磷脂头基的相互作用来稳定。抗原性分析和与病毒粒子表面HIV-1 env电子冷冻断层扫描图像的比较表明，该结构可能代表MPER的预融合构象，不同于几个研究良好的bNAbs靶向的融合中间状态。非常慢的bNab结合表明MPER结构的罕见波动使这些抗体偶尔能够接触到MPER表位的替代构象。MPER的突变不仅阻碍了膜融合，还影响了bNab表位在其他区域的呈现。这些结果建议了开发基于MPER的候选疫苗的策略。
The membrane-proximal external region (MPER) of the HIV-1 envelope glycoprotein (Env) bears epitopes of broadly neutralizing antibodies (bnAbs) from infected individuals; it is thus a potential vaccine target. We report an NMR structure of the MPER and its adjacent transmembrane domain in bicelles that mimic a lipid-bilayer membrane. The MPER lies largely outside the lipid bilayer. It folds into a threefold cluster, stabilized mainly by conserved hydrophobic residues and potentially by interaction with phospholipid headgroups. Antigenic analysis and comparison with published images from electron cryotomography of HIV-1 Env on the virion surface suggest that the structure may represent a prefusion conformation of the MPER, distinct from the fusion-intermediate state targeted by several well-studied bnAbs. Very slow bnAb binding indicates that infrequent fluctuations of the MPER structure give these antibodies occasional access to alternative conformations of MPER epitopes. Mutations in the MPER not only impede membrane fusion but also influence presentation of bnAb epitopes in other regions. These results suggest strategies for developing MPER-based vaccine candidates.