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首页> 外文期刊>Biochemistry >Insights into the Human Glycan Receptor Conformation of 1918 Pandemic Hemagglutinin?Glycan Complexes Derived from Nuclear Magnetic Resonance and Molecular Dynamics Studies
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Insights into the Human Glycan Receptor Conformation of 1918 Pandemic Hemagglutinin?Glycan Complexes Derived from Nuclear Magnetic Resonance and Molecular Dynamics Studies

机译：1918年大流行血凝素的人甘油受体构象的见解？Glycan复合物来自核磁共振和分子动力学研究的衍生

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摘要

The glycan receptor binding and specificity of influenza A viral hemagglutinin (HA) are critical for virus infection and transmission in humans. However, ambiguities in the interpretation of the receptor binding specificity of hemagglutinin from human- and avian-adapted viruses have prevented an understanding of its relationship with aerosol transmissibility, an exclusive property of human-adapted viruses. A previous conformational study, which we performed, indicated that human and avian receptors sample distinct conformations in solution. On the basis of detailed nuclear magnetic resonance (NMR) studies provided herein, we offer evidence of the distinct structural constraints imposed by hemagglutinin receptor binding sites on the glycan conformational space upon binding. The hemagglutinin from the SC18 virus, which has efficient aerosol transmissibility in humans (human-adapted), imposed the most stringent constraints on the conformational space of the human glycan receptor (LSTc), compared to single (NY18) or double (AV18) amino acid HA mutants, a property correlating to the ligand?HA binding strength. This relationship was also observed for the avian-adapted HA, where the high affinity binding partner, AV18, imposed the most stringent conformational constraints on the avian receptor, compared to those imposed by NY18. In particular, it is interesting to observe how different HAs when binding to human or avian glycosidic receptors impose significantly different conformational states, in terms of the states sampled by the glycosidic backbone and/or the entire molecule shape (linear or bent), when compared to the corresponding unbound glycans. Significantly, we delineate a "characteristic NMR signature" for the human adapted hemagglutinin (SC18) binding to human glycan receptors. Therefore, the conformational space constraints imposed by the hemagglutinin receptor binding site provide a characteristic signature that could be a useful tool for the surveillance of human adaptation of other (such as H7N9 and H5N1) deadly influenza viruses.
机译：流感的甘草受体结合和甲型病毒血凝素（HA）的特异性对于人类的病毒感染和传播至关重要。然而，在人和禽类适应病毒中解释血凝素的受体结合特异性的含糊不清已经阻止了理解其与气溶胶传播性的关系，是人类适应病毒的独家财产。我们进行的先前构象研究表明，人和禽类受体在溶液中对不同的构象进行了不同的构象。在本文提供的详细核磁共振（NMR）研究的基础上，我们提供了在结合时血凝素受体结合位点上血凝素受体结合位点施加的不同结构约束的证据。来自人类（人类适应）的SC18病毒的血凝素，具有有效的气溶胶传播性，对单身（NY18）或双（AV18）氨基相比，对人甘油受体（LSTC）的构象空间施加了最严格的限制酸性HA突变体，与配体的性质相关？HA结合强度。与NY18施加的人相比，该关系也针对AVIAN适应的HA观察到禽类适应的HA，其中高亲和力结合伴侣AV18对禽类受体产生最严格的构象约束。特别地，观察与人或禽糖苷受体的结合有多种不同的构象状态有趣，就糖苷骨架和/或整个分子形状（线性或弯曲）进行了相比，相比之下到相应的未结合的聚糖。值得注意的是，我们描绘了人类适应的血凝素（SC18）与人甘油受体结合的“特征NMR签名”。因此，血凝素受体结合位点施加的构象空间约束提供了一种特征签名，这可能是用于监测人类适应其他（例如H7N9和H5N1）致命流感病毒的有用工具。

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  • 来源
    《Biochemistry》 |2014年第25期|共14页
  • 作者

    Stefano Elli; Eleonora Macchi; Timothy R. Rudd; Rahul Raman; Guillherme Sassaki; Karthik Viswanathan; Edwin A. Yates; Zachary Shriver; Annamaria Naggi; Giangiacomo Torri; Ram Sasisekharan; Marco Guerrini;

  • 作者单位

    Istituto di Ricerche Chimiche e Biochimiche "G. Ronzoni" Via Giuseppe Colombo 81 20133 Milano Italy;

    Istituto di Ricerche Chimiche e Biochimiche "G. Ronzoni" Via Giuseppe Colombo 81 20133 Milano Italy;

    Diamond Light Source Ltd. Diamond House Harwell Science and Innovation Campus Didcot Oxfordshire OX11 0DE U.K;

    Department of Biological Engineering Koch Institute of Integrative Cancer Research Massachusetts Institute of Technology 77 Massachusetts Avenue Cambridge Massachusetts 02139 United States;

    Departamento de Bioqu?m? ica e Biologia Molecular Universidade Federal do Parana ? CEP 81.531-980 CP 19046 Curitiba PR Brazil;

    Department of Biological Engineering Koch Institute of Integrative Cancer Research Massachusetts Institute of Technology 77 Massachusetts Avenue Cambridge Massachusetts 02139 United States;

    Department of Structural and Chemical Biology University of Liverpool Liverpool L69 3BX U.K;

    Department of Biological Engineering Koch Institute of Integrative Cancer Research Massachusetts Institute of Technology 77 Massachusetts Avenue Cambridge Massachusetts 02139 United States;

    Istituto di Ricerche Chimiche e Biochimiche "G. Ronzoni" Via Giuseppe Colombo 81 20133 Milano Italy;

    Istituto di Ricerche Chimiche e Biochimiche "G. Ronzoni" Via Giuseppe Colombo 81 20133 Milano Italy;

    Department of Biological Engineering Koch Institute of Integrative Cancer Research Massachusetts Institute of Technology 77 Massachusetts Avenue Cambridge Massachusetts 02139 United States;

    Istituto di Ricerche Chimiche e Biochimiche "G. Ronzoni" Via Giuseppe Colombo 81 20133 Milano Italy;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物化学;
  • 关键词

    Insights; Human Glycan; Receptor Conformation;

    机译：见解;人类聚糖;受体构象;

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