Structural Characterization of the 1918 Influenza Virus H1N1 Neuraminidase
Structural Characterization of the 1918 Influenza Virus H1N1 Neuraminidase
复制标题
DOI：
10.1128/jvi.00959-08
复制
发表时间：
2008-11-01
影响因子：
5.4
通讯作者：
Wilson, Ian A.
中科院分区：
文献类型：
--
作者：
Xu, Xiaojin;Zhu, Xueyong;Wilson, Ian A.
流感病毒神经氨酸酶(NA)在促进新合成病毒在宿主体内传播方面起着至关重要的作用，是控制疾病进展的重要靶点。1918年“西班牙流感”(A/Brevig Space/1/18 H1N1)及其与扎那米韦(瑞乐沙)的复合体的NA晶体结构分别在1.65埃和1.45埃分辨率下证实了正确折叠的NA四聚体在杆状病毒表达系统中的成功表达。与包括H5N1在内的N2和N9 Nas相比，N1中观察到与底物结合部位相邻的额外空腔。这个空腔来自150环(Gly147到Asp151)的开放构象，并且似乎在第1族Nas(N1、N4、N5和N8)中保守。它接近扎那米韦的结合。确定了三个钙位点，其中包括一个可能在N1和N4中保守的新位点。因此，这些高分辨率结构与我们的重组表达系统相结合，为扩大有限的流感治疗药物提供了新的机会。
Influenza virus neuraminidase (NA) plays a crucial role in facilitating the spread of newly synthesized virus in the host and is an important target for controlling disease progression. The NA crystal structure from the 1918 "Spanish flu" (A/Brevig Mission/1/18 H1N1) and that of its complex with zanamivir (Relenza) at 1.65-angstrom and 1.45-angstrom resolutions, respectively, corroborated the successful expression of correctly folded NA tetramers in a baculovirus expression system. An additional cavity adjacent to the substrate-binding site is observed in N1, compared to N2 and N9 NAs, including H5N1. This cavity arises from an open conformation of the 150 loop (Gly147 to Asp151) and appears to be conserved among group 1 NAs ( N1, N4, N5, and N8). It closes upon zanamivir binding. Three calcium sites were identified, including a novel site that may be conserved in N1 and N4. Thus, these high-resolution structures, combined with our recombinant expression system, provide new opportunities to augment the limited arsenal of therapeutics against influenza.