Zeng Qinghong, Langereis Martijn A, van Vliet Arno L W, Huizinga Eric G, de Groot Raoul J
Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Sciences, Utrecht University, 3584 CL, Utrecht, The Netherlands.
Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9065-9. doi: 10.1073/pnas.0800502105. Epub 2008 Jun 11.
The hemagglutinin-esterases (HEs) are a family of viral envelope glycoproteins that mediate reversible attachment to O-acetylated sialic acids by acting both as lectins and as receptor-destroying enzymes (RDEs). Related HEs occur in influenza C, toro-, and coronaviruses, apparently as a result of relatively recent lateral gene transfer events. Here, we report the crystal structure of a coronavirus (CoV) HE in complex with its receptor. We show that CoV HE arose from an influenza C-like HE fusion protein (HEF). In the process, HE was transformed from a trimer into a dimer, whereas remnants of the fusion domain were adapted to establish novel monomer-monomer contacts. Whereas the structural design of the RDE-acetylesterase domain remained unaltered, the HE receptor-binding domain underwent remodeling to such extent that the ligand is now bound in opposite orientation. This is surprising, because the architecture of the HEF site was preserved in influenza A HA over a much larger evolutionary distance, a switch in receptor specificity and extensive antigenic variation notwithstanding. Apparently, HA and HEF are under more stringent selective constraints than HE, limiting their exploration of alternative binding-site topologies. We attribute the plasticity of the CoV HE receptor-binding site to evolutionary flexibility conferred by functional redundancy between HE and its companion spike protein S. Our findings offer unique insights into the structural and functional consequences of independent protein evolution after interviral gene exchange and open potential avenues to broad-spectrum antiviral drug design.
血凝素酯酶（HEs）是一类病毒包膜糖蛋白家族，它们通过作为凝集素和受体破坏酶（RDEs）发挥作用，介导与O-乙酰化唾液酸的可逆结合。相关的HEs存在于丙型流感病毒、环曲病毒和冠状病毒中，显然是相对较新的横向基因转移事件的结果。在此，我们报道了一种冠状病毒（CoV）的HE与其受体复合物的晶体结构。我们表明，CoV HE起源于一种类似丙型流感病毒的HE融合蛋白（HEF）。在此过程中，HE从三聚体转变为二聚体，而融合结构域的残余部分经过调整以建立新的单体-单体接触。虽然RDE-乙酰酯酶结构域的结构设计保持不变，但HE受体结合结构域发生了显著重塑，以至于现在配体以相反方向结合。这令人惊讶，因为尽管存在受体特异性的转变和广泛的抗原变异，但HEF位点的结构在甲型流感病毒血凝素（HA）中在更大的进化距离上得以保留。显然，HA和HEF比HE受到更严格的选择限制，限制了它们对替代结合位点拓扑结构的探索。我们将CoV HE受体结合位点的可塑性归因于HE与其伴侣刺突蛋白S之间功能冗余赋予的进化灵活性。我们的研究结果为病毒间基因交换后独立蛋白质进化的结构和功能后果提供了独特见解，并为广谱抗病毒药物设计开辟了潜在途径。
