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Structure of Venezuelan equine encephalitis virus with its receptor LDLRAD3

Author

Listed:
  • Bingting Ma

    (Tsinghua University)

  • Cuiqing Huang

    (Chinese Academy of Sciences (CAS)
    University of Chinese Academy of Sciences)

  • Jun Ma

    (Chinese Academy of Sciences (CAS))

  • Ye Xiang

    (Tsinghua University)

  • Xinzheng Zhang

    (Chinese Academy of Sciences (CAS)
    University of Chinese Academy of Sciences)

Abstract

Venezuelan equine encephalitis virus (VEEV) is an enveloped RNA virus that causes encephalitis and potentially mortality in infected humans and equines1. At present, no vaccines or drugs are available that prevent or cure diseases caused by VEEV. Low-density lipoprotein receptor class A domain-containing 3 (LDLRAD3) was recently identified as a receptor for the entry of VEEV into host cells2. Here we present the cryo-electron microscopy structure of the LDLRAD3 extracellular domain 1 (LDLRAD3-D1) in complex with VEEV virus-like particles at a resolution of 3.0 Å. LDLRAD3-D1 has a cork-like structure and is inserted into clefts formed between adjacent VEEV E2–E1 heterodimers in the viral-surface trimer spikes through hydrophobic and polar contacts. Mutagenesis studies of LDLRAD3-D1 identified residues that are involved in the key interactions with VEEV. Of note, some of the LDLRAD3-D1 mutants showed a significantly increased binding affinity for VEEV, suggesting that LDLRAD3-D1 may serve as a potential scaffold for the development of inhibitors of VEEV entry. Our structures provide insights into alphavirus assembly and the binding of receptors to alphaviruses, which may guide the development of therapeutic countermeasures against alphaviruses.

Suggested Citation

  • Bingting Ma & Cuiqing Huang & Jun Ma & Ye Xiang & Xinzheng Zhang, 2021. "Structure of Venezuelan equine encephalitis virus with its receptor LDLRAD3," Nature, Nature, vol. 598(7882), pages 677-681, October.
  • Handle: RePEc:nat:nature:v:598:y:2021:i:7882:d:10.1038_s41586-021-03909-1
    DOI: 10.1038/s41586-021-03909-1
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    Cited by:

    1. Xiaofeng Zhai & Xiaoling Li & Michael Veit & Ningning Wang & Yu Wang & Andres Merits & Zhiwen Jiang & Yan Qin & Xiaoguang Zhang & Kaili Qi & Houqi Jiao & Wan-Ting He & Ye Chen & Yang Mao & Shuo Su, 2024. "LDLR is used as a cell entry receptor by multiple alphaviruses," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Duanfang Cao & Bingting Ma & Ziyi Cao & Xiaoyu Xu & Xinzheng Zhang & Ye Xiang, 2024. "The receptor VLDLR binds Eastern Equine Encephalitis virus through multiple distinct modes," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Ningning Wang & Andres Merits & Michael Veit & Laura Sandra Lello & Shuhan Kong & Houqi Jiao & Jie Chen & Yu Wang & Georgi Dobrikov & Félix A. Rey & Shuo Su, 2024. "LDL receptor in alphavirus entry: structural analysis and implications for antiviral therapy," Nature Communications, Nature, vol. 15(1), pages 1-7, December.
    4. Pan Yang & Wanyu Li & Xiaoyi Fan & Junhua Pan & Colin J. Mann & Haley Varnum & Lars E. Clark & Sarah A. Clark & Adrian Coscia & Himanish Basu & Katherine Nabel Smith & Vesna Brusic & Jonathan Abraham, 2024. "Structural basis for VLDLR recognition by eastern equine encephalitis virus," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    5. Hongming Ma & Lucas J. Adams & Saravanan Raju & Alan Sariol & Natasha M. Kafai & Hana Janova & William B. Klimstra & Daved H. Fremont & Michael S. Diamond, 2024. "The low-density lipoprotein receptor promotes infection of multiple encephalitic alphaviruses," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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