Structure of herpes simplex virus glycoprotein D bound to the human receptor nectin-1.
Structure of herpes simplex virus glycoprotein D bound to the human receptor nectin-1.
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DOI：
10.1371/journal.ppat.1002277
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发表时间：
2011-09
期刊：
影响因子：
6.7
通讯作者：
Carfi A
中科院分区：
文献类型：
--
作者：
Di Giovine P;Settembre EC;Bhargava AK;Luftig MA;Lou H;Cohen GH;Eisenberg RJ;Krummenacher C;Carfi A
单纯疱疹病毒(HSV)糖蛋白D(GD)在进入宿主细胞时需要与细胞表面受体结合才能触发膜融合。Nectin-1是一种细胞黏附分子，是神经元和上皮细胞中的主要HSV受体。我们报道了用X-射线结晶学方法确定的与Nectin-1结合的Gd的结构。该结构表明，GD上的Nectin-1结合部位与HVEM受体的结合部位不同。在Nectin-1的第一个Ig结构域上的一个表面，它介导了Ig样细胞黏附分子的同亲相互作用，掩埋了一个由GDN-末端和C-末端延伸的残基组成的区域。在连接Nectin-1的β链F和G的环的末端，苯丙氨酸129突出到GD上的一个凹槽中，否则被未连接的GD中的C-末端残基和GD/HVEM复合体中的N-末端残基占据。值得注意的是，Phe129突变为丙氨酸，阻止了Nextin-1与GD和HSV进入。总而言之，这些数据与之前的研究一致，这些研究表明GD扰乱了正常的Nextin-1亲和性相互作用。此外，该复合体的结构支持一种模型，在该模型中，gD受体结合通过受体介导的GdC末端区域的移位来触发HSV进入。
Binding of herpes simplex virus (HSV) glycoprotein D (gD) to a cell surface receptor is required to trigger membrane fusion during entry into host cells. Nectin-1 is a cell adhesion molecule and the main HSV receptor in neurons and epithelial cells. We report the structure of gD bound to nectin-1 determined by x-ray crystallography to 4.0 Å resolution. The structure reveals that the nectin-1 binding site on gD differs from the binding site of the HVEM receptor. A surface on the first Ig-domain of nectin-1, which mediates homophilic interactions of Ig-like cell adhesion molecules, buries an area composed by residues from both the gD N- and C-terminal extensions. Phenylalanine 129, at the tip of the loop connecting β-strands F and G of nectin-1, protrudes into a groove on gD, which is otherwise occupied by C-terminal residues in the unliganded gD and by N-terminal residues in the gD/HVEM complex. Notably, mutation of Phe129 to alanine prevents nectin-1 binding to gD and HSV entry. Together these data are consistent with previous studies showing that gD disrupts the normal nectin-1 homophilic interactions. Furthermore, the structure of the complex supports a model in which gD-receptor binding triggers HSV entry through receptor-mediated displacement of the gD C-terminal region.
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