Novel Intersubunit Interaction Critical for HIV-1 Core Assembly Defines a Potentially Targetable Inhibitor Binding Pocket

ABSTRACT HIV-1 capsid protein (CA) plays critical roles in both early and late stages of the viral replication cycle. Mutagenesis and structural experiments have revealed that capsid core stability significantly affects uncoating and initiation of reverse transcription in host cells. This has led to...

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Autores principales:	Pierrick Craveur, Anna T. Gres, Karen A. Kirby, Dandan Liu, John A. Hammond, Yisong Deng, Stefano Forli, David S. Goodsell, James R. Williamson, Stefan G. Sarafianos, Arthur J. Olson
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	X-ray crystallography capsid capsid assembly computer modeling human immunodeficiency virus Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/2c7248c5c5474ef89cde7e5cef479355
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spelling	oai:doaj.org-article:2c7248c5c5474ef89cde7e5cef4793552021-11-15T15:55:25ZNovel Intersubunit Interaction Critical for HIV-1 Core Assembly Defines a Potentially Targetable Inhibitor Binding Pocket10.1128/mBio.02858-182150-7511https://doaj.org/article/2c7248c5c5474ef89cde7e5cef4793552019-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02858-18https://doaj.org/toc/2150-7511ABSTRACT HIV-1 capsid protein (CA) plays critical roles in both early and late stages of the viral replication cycle. Mutagenesis and structural experiments have revealed that capsid core stability significantly affects uncoating and initiation of reverse transcription in host cells. This has led to efforts in developing antivirals targeting CA and its assembly, although none of the currently identified compounds are used in the clinic for treatment of HIV infection. A specific interaction that is primarily present in pentameric interfaces in the HIV-1 capsid core was identified and is reported to be important for CA assembly. This is shown by multidisciplinary characterization of CA site-directed mutants using biochemical analysis of virus-like particle formation, transmission electron microscopy of in vitro assembly, crystallographic studies, and molecular dynamic simulations. The data are consistent with a model where a hydrogen bond between CA residues E28 and K30′ from neighboring N-terminal domains (CANTDs) is important for CA pentamer interactions during core assembly. This pentamer-preferred interaction forms part of an N-terminal domain interface (NDI) pocket that is amenable to antiviral targeting. IMPORTANCE Precise assembly and disassembly of the HIV-1 capsid core are key to the success of viral replication. The forces that govern capsid core formation and dissociation involve intricate interactions between pentamers and hexamers formed by HIV-1 CA. We identified one particular interaction between E28 of one CA and K30′ of the adjacent CA that appears more frequently in pentamers than in hexamers and that is important for capsid assembly. Targeting the corresponding site could lead to the development of antivirals which disrupt this interaction and affect capsid assembly.Pierrick CraveurAnna T. GresKaren A. KirbyDandan LiuJohn A. HammondYisong DengStefano ForliDavid S. GoodsellJames R. WilliamsonStefan G. SarafianosArthur J. OlsonAmerican Society for MicrobiologyarticleX-ray crystallographycapsidcapsid assemblycomputer modelinghuman immunodeficiency virusMicrobiologyQR1-502ENmBio, Vol 10, Iss 2 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	X-ray crystallography capsid capsid assembly computer modeling human immunodeficiency virus Microbiology QR1-502
spellingShingle	X-ray crystallography capsid capsid assembly computer modeling human immunodeficiency virus Microbiology QR1-502 Pierrick Craveur Anna T. Gres Karen A. Kirby Dandan Liu John A. Hammond Yisong Deng Stefano Forli David S. Goodsell James R. Williamson Stefan G. Sarafianos Arthur J. Olson Novel Intersubunit Interaction Critical for HIV-1 Core Assembly Defines a Potentially Targetable Inhibitor Binding Pocket
description	ABSTRACT HIV-1 capsid protein (CA) plays critical roles in both early and late stages of the viral replication cycle. Mutagenesis and structural experiments have revealed that capsid core stability significantly affects uncoating and initiation of reverse transcription in host cells. This has led to efforts in developing antivirals targeting CA and its assembly, although none of the currently identified compounds are used in the clinic for treatment of HIV infection. A specific interaction that is primarily present in pentameric interfaces in the HIV-1 capsid core was identified and is reported to be important for CA assembly. This is shown by multidisciplinary characterization of CA site-directed mutants using biochemical analysis of virus-like particle formation, transmission electron microscopy of in vitro assembly, crystallographic studies, and molecular dynamic simulations. The data are consistent with a model where a hydrogen bond between CA residues E28 and K30′ from neighboring N-terminal domains (CANTDs) is important for CA pentamer interactions during core assembly. This pentamer-preferred interaction forms part of an N-terminal domain interface (NDI) pocket that is amenable to antiviral targeting. IMPORTANCE Precise assembly and disassembly of the HIV-1 capsid core are key to the success of viral replication. The forces that govern capsid core formation and dissociation involve intricate interactions between pentamers and hexamers formed by HIV-1 CA. We identified one particular interaction between E28 of one CA and K30′ of the adjacent CA that appears more frequently in pentamers than in hexamers and that is important for capsid assembly. Targeting the corresponding site could lead to the development of antivirals which disrupt this interaction and affect capsid assembly.
format	article
author	Pierrick Craveur Anna T. Gres Karen A. Kirby Dandan Liu John A. Hammond Yisong Deng Stefano Forli David S. Goodsell James R. Williamson Stefan G. Sarafianos Arthur J. Olson
author_facet	Pierrick Craveur Anna T. Gres Karen A. Kirby Dandan Liu John A. Hammond Yisong Deng Stefano Forli David S. Goodsell James R. Williamson Stefan G. Sarafianos Arthur J. Olson
author_sort	Pierrick Craveur
title	Novel Intersubunit Interaction Critical for HIV-1 Core Assembly Defines a Potentially Targetable Inhibitor Binding Pocket
title_short	Novel Intersubunit Interaction Critical for HIV-1 Core Assembly Defines a Potentially Targetable Inhibitor Binding Pocket
title_full	Novel Intersubunit Interaction Critical for HIV-1 Core Assembly Defines a Potentially Targetable Inhibitor Binding Pocket
title_fullStr	Novel Intersubunit Interaction Critical for HIV-1 Core Assembly Defines a Potentially Targetable Inhibitor Binding Pocket
title_full_unstemmed	Novel Intersubunit Interaction Critical for HIV-1 Core Assembly Defines a Potentially Targetable Inhibitor Binding Pocket
title_sort	novel intersubunit interaction critical for hiv-1 core assembly defines a potentially targetable inhibitor binding pocket
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/2c7248c5c5474ef89cde7e5cef479355
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Novel Intersubunit Interaction Critical for HIV-1 Core Assembly Defines a Potentially Targetable Inhibitor Binding Pocket

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