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Structure of Venezuelan equine encephalitis virus in complex with the LDLRAD3 receptor
LDLRAD3 is a recently defined attachment and entry receptor for Venezuelan equine encephalitis virus (VEEV)(1), a New World alphavirus that causes severe neurological disease in humans. Here we present near-atomic-resolution cryo-electron microscopy reconstructions of VEEV virus-like particles alone...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8550936/ https://www.ncbi.nlm.nih.gov/pubmed/34646020 http://dx.doi.org/10.1038/s41586-021-03963-9 |
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author | Basore, Katherine Ma, Hongming Kafai, Natasha M. Mackin, Samantha Kim, Arthur S. Nelson, Christopher A. Diamond, Michael S. Fremont, Daved H. |
author_facet | Basore, Katherine Ma, Hongming Kafai, Natasha M. Mackin, Samantha Kim, Arthur S. Nelson, Christopher A. Diamond, Michael S. Fremont, Daved H. |
author_sort | Basore, Katherine |
collection | PubMed |
description | LDLRAD3 is a recently defined attachment and entry receptor for Venezuelan equine encephalitis virus (VEEV)(1), a New World alphavirus that causes severe neurological disease in humans. Here we present near-atomic-resolution cryo-electron microscopy reconstructions of VEEV virus-like particles alone and in a complex with the ectodomains of LDLRAD3. Domain 1 of LDLRAD3 is a low-density lipoprotein receptor type-A module that binds to VEEV by wedging into a cleft created by two adjacent E2–E1 heterodimers in one trimeric spike, and engages domains A and B of E2 and the fusion loop in E1. Atomic modelling of this interface is supported by mutagenesis and anti-VEEV antibody binding competition assays. Notably, VEEV engages LDLRAD3 in a manner that is similar to the way that arthritogenic alphaviruses bind to the structurally unrelated MXRA8 receptor, but with a much smaller interface. These studies further elucidate the structural basis of alphavirus–receptor interactions, which could inform the development of therapies to mitigate infection and disease against multiple members of this family. |
format | Online Article Text |
id | pubmed-8550936 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-85509362021-11-10 Structure of Venezuelan equine encephalitis virus in complex with the LDLRAD3 receptor Basore, Katherine Ma, Hongming Kafai, Natasha M. Mackin, Samantha Kim, Arthur S. Nelson, Christopher A. Diamond, Michael S. Fremont, Daved H. Nature Article LDLRAD3 is a recently defined attachment and entry receptor for Venezuelan equine encephalitis virus (VEEV)(1), a New World alphavirus that causes severe neurological disease in humans. Here we present near-atomic-resolution cryo-electron microscopy reconstructions of VEEV virus-like particles alone and in a complex with the ectodomains of LDLRAD3. Domain 1 of LDLRAD3 is a low-density lipoprotein receptor type-A module that binds to VEEV by wedging into a cleft created by two adjacent E2–E1 heterodimers in one trimeric spike, and engages domains A and B of E2 and the fusion loop in E1. Atomic modelling of this interface is supported by mutagenesis and anti-VEEV antibody binding competition assays. Notably, VEEV engages LDLRAD3 in a manner that is similar to the way that arthritogenic alphaviruses bind to the structurally unrelated MXRA8 receptor, but with a much smaller interface. These studies further elucidate the structural basis of alphavirus–receptor interactions, which could inform the development of therapies to mitigate infection and disease against multiple members of this family. Nature Publishing Group UK 2021-10-13 2021 /pmc/articles/PMC8550936/ /pubmed/34646020 http://dx.doi.org/10.1038/s41586-021-03963-9 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Basore, Katherine Ma, Hongming Kafai, Natasha M. Mackin, Samantha Kim, Arthur S. Nelson, Christopher A. Diamond, Michael S. Fremont, Daved H. Structure of Venezuelan equine encephalitis virus in complex with the LDLRAD3 receptor |
title | Structure of Venezuelan equine encephalitis virus in complex with the LDLRAD3 receptor |
title_full | Structure of Venezuelan equine encephalitis virus in complex with the LDLRAD3 receptor |
title_fullStr | Structure of Venezuelan equine encephalitis virus in complex with the LDLRAD3 receptor |
title_full_unstemmed | Structure of Venezuelan equine encephalitis virus in complex with the LDLRAD3 receptor |
title_short | Structure of Venezuelan equine encephalitis virus in complex with the LDLRAD3 receptor |
title_sort | structure of venezuelan equine encephalitis virus in complex with the ldlrad3 receptor |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8550936/ https://www.ncbi.nlm.nih.gov/pubmed/34646020 http://dx.doi.org/10.1038/s41586-021-03963-9 |
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