Lentz K N, Smith A D, Geisler S C, Cox S, Buontempo P, Skelton A, DeMartino J, Rozhon E, Schwartz J, Girijavallabhan V, O'Connell J, Arnold E
Center for Advanced Biotechnology and Medicine, Piscataway, NJ 08854, USA.
Structure. 1997 Jul 15;5(7):961-78. doi: 10.1016/s0969-2126(97)00249-9.
Polioviruses are human pathogens and the causative agents of poliomyelitis. Polioviruses are icosahedral single-stranded RNA viruses, which belong to the picornavirus family, and occur as three distinct serotypes. All three serotypes of poliovirus can infect primates, but only type 2 can infect mice. The crystal structures of a type 1 and a type 3 poliovirus are already known. Structural studies of poliovirus type 2 Lansing (PV2L) were initiated to try to enhance our understanding of the differences in host range specificity, antigenicity and receptor binding among the three serotypes of poliovirus.
The crystal structure of the mouse neurovirulent PV2L complexed with a potent antiviral agent, SCH48973, was determined at 2.9 A resolution. Structural differences among the three poliovirus serotypes occur primarily in the loop regions of the viral coat proteins (VPs), most notably in the loops of VP1 that cluster near the fivefold axes of the capsid, where the BC loop of PV2L is disordered. Unlike other known structures of enteroviruses, the entire polypeptide chain of PV2L VP4 is visible in the electron density and RNA bases are observed stacking with conserved aromatic residues (Tyr4020 and Phe4046) of VP4. The broad-spectrum antiviral agent SCH48973 is observed binding in a pocket within the beta-barrel of VP1, in approximately the same location that natural 'pocket factors' bind to polioviruses. SCH48973 forms predominantly hydrophobic interactions with the pocket residues.
Some of the conformational changes required for infectivity and involved in the control of capsid stability and neurovirulence in mice may occur in the vicinity of the fivefold axis of the poliovirus, where there are significant structural differences among the three poliovirus serotypes in the surface exposed loops of VP1 (BC, DE, and HI). A surface depression is located at the fivefold axis of PV2L that is not present in the other two poliovirus serotypes. The observed interaction of RNA with VP4 supports the observation that loss of VP4 ultimately leads to the loss of viral RNA. A model is proposed that suggests dual involvement of the virion fivefold and pseudo-threefold axes in receptor-mediated initiation of infection by picornaviruses.
脊髓灰质炎病毒是人类病原体，也是脊髓灰质炎的致病因子。脊髓灰质炎病毒是二十面体单链RNA病毒，属于微小核糖核酸病毒科，有三种不同的血清型。脊髓灰质炎病毒的所有三种血清型都能感染灵长类动物，但只有2型能感染小鼠。1型和3型脊髓灰质炎病毒的晶体结构已为人所知。开展对2型兰辛脊髓灰质炎病毒（PV2L）的结构研究，旨在增进我们对脊髓灰质炎病毒三种血清型在宿主范围特异性、抗原性和受体结合方面差异的理解。
以2.9埃的分辨率确定了与强效抗病毒剂SCH48973复合的小鼠神经毒性PV2L的晶体结构。三种脊髓灰质炎病毒血清型之间的结构差异主要发生在病毒衣壳蛋白（VPs）的环区，最显著的是在衣壳五重轴附近聚集的VP1环区，其中PV2L的BC环无序。与其他已知的肠道病毒结构不同，PV2L VP4的整个多肽链在电子密度图中可见，并且观察到RNA碱基与VP4的保守芳香族残基（Tyr4020和Phe4046）堆积。观察到广谱抗病毒剂SCH48973结合在VP1β桶内的一个口袋中，位置与天然“口袋因子”结合脊髓灰质炎病毒的位置大致相同。SCH48973主要与口袋残基形成疏水相互作用。
感染所需的以及参与小鼠衣壳稳定性和神经毒性控制的一些构象变化可能发生在脊髓灰质炎病毒五重轴附近，在VP1（BC、DE和HI）表面暴露环区，三种脊髓灰质炎病毒血清型在此处存在显著结构差异。PV2L的五重轴处有一个表面凹陷，其他两种脊髓灰质炎病毒血清型中不存在。观察到的RNA与VP4的相互作用支持了VP4缺失最终导致病毒RNA缺失的观点。提出了一个模型，表明病毒体五重轴和假三重轴在微小核糖核酸病毒受体介导的感染起始中起双重作用。
