Crennell S, Takimoto T, Portner A, Taylor G
Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK.
Nat Struct Biol. 2000 Nov;7(11):1068-74. doi: 10.1038/81002.
Paramyxoviruses are the main cause of respiratory disease in children. One of two viral surface glycoproteins, the hemagglutinin-neuraminidase (HN), has several functions in addition to being the major surface antigen that induces neutralizing antibodies. Here we present the crystal structures of Newcastle disease virus HN alone and in complex with either an inhibitor or with the beta-anomer of sialic acid. The inhibitor complex reveals a typical neuraminidase active site within a beta-propeller fold. Comparison of the structures of the two complexes reveal differences in the active site, suggesting that the catalytic site is activated by a conformational switch. This site may provide both sialic acid binding and hydrolysis functions since there is no evidence for a second sialic acid binding site in HN. Evidence for a single site with dual functions is examined and supported by mutagenesis studies. The structure provides the basis for the structure-based design of inhibitors for a range of paramyxovirus-induced diseases.
副粘病毒是儿童呼吸道疾病的主要病因。两种病毒表面糖蛋白之一，即血凝素神经氨酸酶（HN），除了作为诱导中和抗体的主要表面抗原外，还具有多种功能。在此，我们展示了新城疫病毒HN单独的晶体结构，以及与抑制剂或唾液酸β-异头物形成复合物的晶体结构。抑制剂复合物在β-螺旋桨折叠结构内揭示了一个典型的神经氨酸酶活性位点。两种复合物结构的比较揭示了活性位点的差异，表明催化位点通过构象转换被激活。由于在HN中没有第二个唾液酸结合位点的证据，该位点可能同时提供唾液酸结合和水解功能。通过诱变研究检验并支持了单一位点具有双重功能的证据。该结构为一系列副粘病毒引起的疾病的抑制剂基于结构的设计提供了基础。
