犬瘟热病毒(CDV)属于麻疹病毒,包括麻疹病毒(MeV)和牛瘟病毒,导致食肉动物严重的免疫和神经系统疾病,包括狗和恒河猴,正如最近报道的那样,但是他们的疫苗非常有效。CDV表面的附着糖蛋白血凝素(CDV-H)利用信号淋巴细胞激活分子(SLAM)和Nectin-4(也称为脊髓灰质炎病毒受体样4;PVRL4)作为进入受体。尽管已经提出了融合模型,对麻疹病毒融合进入的分子机制了解甚少。这里,我们确定了CDV-H疫苗株球形头域的晶体结构,分辨率为3.2。揭示CDV-H表现出高度倾斜的同二聚体形式,具有六叶片β螺旋桨折叠。虽然预测的Nectin-4结合位点与MeV-H非常保守,SLAM的相似但部分不同,这有望有助于宿主特异性。五种N-连接的糖覆盖了CDV-H表面的广阔区域,仅暴露受体结合位点,支持中和抗体的有效生产。这些功能是MeV-H所共有的,虽然糖基化位点是完全不同的。此外,使用高速原子力显微镜的实时观察揭示了通过连接器区域的CDV-H二聚体头的高度移动特征。这些结果表明,糖屏蔽的倾斜同二聚体结构和动态构象变化是麻疹病毒的共同特征,并确保有效的融合进入和疫苗接种。
Canine distemper virus (CDV) belongs to morbillivirus, including measles virus (MeV) and rinderpest virus, which causes serious immunological and neurological disorders in carnivores, including dogs and rhesus monkeys, as recently reported, but their vaccines are highly effective. The attachment glycoprotein hemagglutinin (CDV-H) at the CDV surface utilizes signaling lymphocyte activation molecule (SLAM) and Nectin-4 (also called poliovirus-receptor-like-4; PVRL4) as entry receptors. Although fusion models have been proposed, the molecular mechanism of morbillivirus fusion entry is poorly understood. Here, we determined the crystal structure of the globular head domain of CDV-H vaccine strain at 3.2 Å resolution, revealing that CDV-H exhibits a highly tilted homodimeric form with a six-bladed β-propeller fold. While the predicted Nectin-4-binding site is well conserved with that of MeV-H, that of SLAM is similar but partially different, which is expected to contribute to host specificity. Five N-linked sugars covered a broad area of the CDV-H surface to expose receptor-binding sites only, supporting the effective production of neutralizing antibodies. These features are common to MeV-H, although the glycosylation sites are completely different. Furthermore, real-time observation using high-speed atomic force microscopy revealed highly mobile features of the CDV-H dimeric head via the connector region. These results suggest that sugar-shielded tilted homodimeric structure and dynamic conformational changes are common characteristics of morbilliviruses and ensure effective fusion entry and vaccination.