Structural bases of coronavirus attachment to host aminopeptidase N and its inhibition by neutralizing antibodies.

The coronaviruses (CoVs) are enveloped viruses of animals and humans associated mostly with enteric and respiratory diseases, such as the severe acute respiratory syndrome and 10-20% of all common colds. A subset of CoVs uses the cell surface aminopeptidase N (APN), a membrane-bound metalloprotease,...

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Autores principales:	Juan Reguera, César Santiago, Gaurav Mudgal, Desiderio Ordoño, Luis Enjuanes, José M Casasnovas
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/09121afb96c04366991a2c8c63c85b2d
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spelling	oai:doaj.org-article:09121afb96c04366991a2c8c63c85b2d2021-11-18T06:04:07ZStructural bases of coronavirus attachment to host aminopeptidase N and its inhibition by neutralizing antibodies.1553-73661553-737410.1371/journal.ppat.1002859https://doaj.org/article/09121afb96c04366991a2c8c63c85b2d2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22876187/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374The coronaviruses (CoVs) are enveloped viruses of animals and humans associated mostly with enteric and respiratory diseases, such as the severe acute respiratory syndrome and 10-20% of all common colds. A subset of CoVs uses the cell surface aminopeptidase N (APN), a membrane-bound metalloprotease, as a cell entry receptor. In these viruses, the envelope spike glycoprotein (S) mediates the attachment of the virus particles to APN and subsequent cell entry, which can be blocked by neutralizing antibodies. Here we describe the crystal structures of the receptor-binding domains (RBDs) of two closely related CoV strains, transmissible gastroenteritis virus (TGEV) and porcine respiratory CoV (PRCV), in complex with their receptor, porcine APN (pAPN), or with a neutralizing antibody. The data provide detailed information on the architecture of the dimeric pAPN ectodomain and its interaction with the CoV S. We show that a protruding receptor-binding edge in the S determines virus-binding specificity for recessed glycan-containing surfaces in the membrane-distal region of the pAPN ectodomain. Comparison of the RBDs of TGEV and PRCV to those of other related CoVs, suggests that the conformation of the S receptor-binding region determines cell entry receptor specificity. Moreover, the receptor-binding edge is a major antigenic determinant in the TGEV envelope S that is targeted by neutralizing antibodies. Our results provide a compelling view on CoV cell entry and immune neutralization, and may aid the design of antivirals or CoV vaccines. APN is also considered a target for cancer therapy and its structure, reported here, could facilitate the development of anti-cancer drugs.Juan RegueraCésar SantiagoGaurav MudgalDesiderio OrdoñoLuis EnjuanesJosé M CasasnovasPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 8, Iss 8, p e1002859 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Juan Reguera César Santiago Gaurav Mudgal Desiderio Ordoño Luis Enjuanes José M Casasnovas Structural bases of coronavirus attachment to host aminopeptidase N and its inhibition by neutralizing antibodies.
description	The coronaviruses (CoVs) are enveloped viruses of animals and humans associated mostly with enteric and respiratory diseases, such as the severe acute respiratory syndrome and 10-20% of all common colds. A subset of CoVs uses the cell surface aminopeptidase N (APN), a membrane-bound metalloprotease, as a cell entry receptor. In these viruses, the envelope spike glycoprotein (S) mediates the attachment of the virus particles to APN and subsequent cell entry, which can be blocked by neutralizing antibodies. Here we describe the crystal structures of the receptor-binding domains (RBDs) of two closely related CoV strains, transmissible gastroenteritis virus (TGEV) and porcine respiratory CoV (PRCV), in complex with their receptor, porcine APN (pAPN), or with a neutralizing antibody. The data provide detailed information on the architecture of the dimeric pAPN ectodomain and its interaction with the CoV S. We show that a protruding receptor-binding edge in the S determines virus-binding specificity for recessed glycan-containing surfaces in the membrane-distal region of the pAPN ectodomain. Comparison of the RBDs of TGEV and PRCV to those of other related CoVs, suggests that the conformation of the S receptor-binding region determines cell entry receptor specificity. Moreover, the receptor-binding edge is a major antigenic determinant in the TGEV envelope S that is targeted by neutralizing antibodies. Our results provide a compelling view on CoV cell entry and immune neutralization, and may aid the design of antivirals or CoV vaccines. APN is also considered a target for cancer therapy and its structure, reported here, could facilitate the development of anti-cancer drugs.
format	article
author	Juan Reguera César Santiago Gaurav Mudgal Desiderio Ordoño Luis Enjuanes José M Casasnovas
author_facet	Juan Reguera César Santiago Gaurav Mudgal Desiderio Ordoño Luis Enjuanes José M Casasnovas
author_sort	Juan Reguera
title	Structural bases of coronavirus attachment to host aminopeptidase N and its inhibition by neutralizing antibodies.
title_short	Structural bases of coronavirus attachment to host aminopeptidase N and its inhibition by neutralizing antibodies.
title_full	Structural bases of coronavirus attachment to host aminopeptidase N and its inhibition by neutralizing antibodies.
title_fullStr	Structural bases of coronavirus attachment to host aminopeptidase N and its inhibition by neutralizing antibodies.
title_full_unstemmed	Structural bases of coronavirus attachment to host aminopeptidase N and its inhibition by neutralizing antibodies.
title_sort	structural bases of coronavirus attachment to host aminopeptidase n and its inhibition by neutralizing antibodies.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/09121afb96c04366991a2c8c63c85b2d
work_keys_str_mv	AT juanreguera structuralbasesofcoronavirusattachmenttohostaminopeptidasenanditsinhibitionbyneutralizingantibodies AT cesarsantiago structuralbasesofcoronavirusattachmenttohostaminopeptidasenanditsinhibitionbyneutralizingantibodies AT gauravmudgal structuralbasesofcoronavirusattachmenttohostaminopeptidasenanditsinhibitionbyneutralizingantibodies AT desiderioordono structuralbasesofcoronavirusattachmenttohostaminopeptidasenanditsinhibitionbyneutralizingantibodies AT luisenjuanes structuralbasesofcoronavirusattachmenttohostaminopeptidasenanditsinhibitionbyneutralizingantibodies AT josemcasasnovas structuralbasesofcoronavirusattachmenttohostaminopeptidasenanditsinhibitionbyneutralizingantibodies
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Structural bases of coronavirus attachment to host aminopeptidase N and its inhibition by neutralizing antibodies.

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