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Ebola Viral Glycoprotein Bound to Its Endosomal Receptor Niemann-Pick C1

Filoviruses, including Ebola and Marburg, cause fatal hemorrhagic fever in humans and primates. Understanding how these viruses enter host cells could help to develop effective therapeutics. An endosomal protein, Niemann-Pick C1 (NPC1), has been identified as a necessary entry receptor for this proc...

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Autores principales: Wang, Han, Shi, Yi, Song, Jian, Qi, Jianxun, Lu, Guangwen, Yan, Jinghua, Gao, George F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7111281/
https://www.ncbi.nlm.nih.gov/pubmed/26771495
http://dx.doi.org/10.1016/j.cell.2015.12.044
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author Wang, Han
Shi, Yi
Song, Jian
Qi, Jianxun
Lu, Guangwen
Yan, Jinghua
Gao, George F.
author_facet Wang, Han
Shi, Yi
Song, Jian
Qi, Jianxun
Lu, Guangwen
Yan, Jinghua
Gao, George F.
author_sort Wang, Han
collection PubMed
description Filoviruses, including Ebola and Marburg, cause fatal hemorrhagic fever in humans and primates. Understanding how these viruses enter host cells could help to develop effective therapeutics. An endosomal protein, Niemann-Pick C1 (NPC1), has been identified as a necessary entry receptor for this process, and priming of the viral glycoprotein (GP) to a fusion-competent state is a prerequisite for NPC1 binding. Here, we have determined the crystal structure of the primed GP (GPcl) of Ebola virus bound to domain C of NPC1 (NPC1-C) at a resolution of 2.3 Å. NPC1-C utilizes two protruding loops to engage a hydrophobic cavity on head of GPcl. Upon enzymatic cleavage and NPC1-C binding, conformational change in the GPcl further affects the state of the internal fusion loop, triggering membrane fusion. Our data therefore provide structural insights into filovirus entry in the late endosome and the molecular basis for design of therapeutic inhibitors of viral entry.
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spelling pubmed-71112812020-04-02 Ebola Viral Glycoprotein Bound to Its Endosomal Receptor Niemann-Pick C1 Wang, Han Shi, Yi Song, Jian Qi, Jianxun Lu, Guangwen Yan, Jinghua Gao, George F. Cell Article Filoviruses, including Ebola and Marburg, cause fatal hemorrhagic fever in humans and primates. Understanding how these viruses enter host cells could help to develop effective therapeutics. An endosomal protein, Niemann-Pick C1 (NPC1), has been identified as a necessary entry receptor for this process, and priming of the viral glycoprotein (GP) to a fusion-competent state is a prerequisite for NPC1 binding. Here, we have determined the crystal structure of the primed GP (GPcl) of Ebola virus bound to domain C of NPC1 (NPC1-C) at a resolution of 2.3 Å. NPC1-C utilizes two protruding loops to engage a hydrophobic cavity on head of GPcl. Upon enzymatic cleavage and NPC1-C binding, conformational change in the GPcl further affects the state of the internal fusion loop, triggering membrane fusion. Our data therefore provide structural insights into filovirus entry in the late endosome and the molecular basis for design of therapeutic inhibitors of viral entry. Elsevier Inc. 2016-01-14 2016-01-14 /pmc/articles/PMC7111281/ /pubmed/26771495 http://dx.doi.org/10.1016/j.cell.2015.12.044 Text en Copyright © 2016 Elsevier Inc. All rights reserved. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
spellingShingle Article
Wang, Han
Shi, Yi
Song, Jian
Qi, Jianxun
Lu, Guangwen
Yan, Jinghua
Gao, George F.
Ebola Viral Glycoprotein Bound to Its Endosomal Receptor Niemann-Pick C1
title Ebola Viral Glycoprotein Bound to Its Endosomal Receptor Niemann-Pick C1
title_full Ebola Viral Glycoprotein Bound to Its Endosomal Receptor Niemann-Pick C1
title_fullStr Ebola Viral Glycoprotein Bound to Its Endosomal Receptor Niemann-Pick C1
title_full_unstemmed Ebola Viral Glycoprotein Bound to Its Endosomal Receptor Niemann-Pick C1
title_short Ebola Viral Glycoprotein Bound to Its Endosomal Receptor Niemann-Pick C1
title_sort ebola viral glycoprotein bound to its endosomal receptor niemann-pick c1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7111281/
https://www.ncbi.nlm.nih.gov/pubmed/26771495
http://dx.doi.org/10.1016/j.cell.2015.12.044
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