In:
PLOS Biology, Public Library of Science (PLoS), Vol. 18, No. 12 ( 2020-12-17), p. e3001015-
Abstract:
Reverse transcription, an essential event in the HIV-1 life cycle, requires deoxynucleotide triphosphates (dNTPs) to fuel DNA synthesis, thus requiring penetration of dNTPs into the viral capsid. The central cavity of the capsid protein (CA) hexamer reveals itself as a plausible channel that allows the passage of dNTPs into assembled capsids. Nevertheless, the molecular mechanism of nucleotide import into the capsid remains unknown. Employing all-atom molecular dynamics (MD) simulations, we established that cooperative binding between nucleotides inside a CA hexamer cavity results in energetically favorable conditions for passive translocation of dNTPs into the HIV-1 capsid. Furthermore, binding of the host cell metabolite inositol hexakisphosphate (IP 6 ) enhances dNTP import, while binding of synthesized molecules like benzenehexacarboxylic acid (BHC) inhibits it. The enhancing effect on reverse transcription by IP 6 and the consequences of interactions between CA and nucleotides were corroborated using atomic force microscopy, transmission electron microscopy, and virological assays. Collectively, our results provide an atomistic description of the permeability of the HIV-1 capsid to small molecules and reveal a novel mechanism for the involvement of metabolites in HIV-1 capsid stabilization, nucleotide import, and reverse transcription.
Type of Medium:
Online Resource
ISSN:
1545-7885
DOI:
10.1371/journal.pbio.3001015
DOI:
10.1371/journal.pbio.3001015.g001
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10.1371/journal.pbio.3001015.g002
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10.1371/journal.pbio.3001015.g003
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10.1371/journal.pbio.3001015.g004
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10.1371/journal.pbio.3001015.g005
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10.1371/journal.pbio.3001015.s001
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10.1371/journal.pbio.3001015.s002
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10.1371/journal.pbio.3001015.s003
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10.1371/journal.pbio.3001015.s004
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10.1371/journal.pbio.3001015.s005
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10.1371/journal.pbio.3001015.s006
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10.1371/journal.pbio.3001015.s007
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10.1371/journal.pbio.3001015.s008
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10.1371/journal.pbio.3001015.s009
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10.1371/journal.pbio.3001015.s010
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10.1371/journal.pbio.3001015.s011
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10.1371/journal.pbio.3001015.s012
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10.1371/journal.pbio.3001015.s013
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10.1371/journal.pbio.3001015.s014
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10.1371/journal.pbio.3001015.s015
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10.1371/journal.pbio.3001015.s016
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10.1371/journal.pbio.3001015.s017
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10.1371/journal.pbio.3001015.s018
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10.1371/journal.pbio.3001015.s019
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10.1371/journal.pbio.3001015.s020
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10.1371/journal.pbio.3001015.s021
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10.1371/journal.pbio.3001015.s022
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10.1371/journal.pbio.3001015.s023
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10.1371/journal.pbio.3001015.s024
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10.1371/journal.pbio.3001015.s025
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10.1371/journal.pbio.3001015.s026
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10.1371/journal.pbio.3001015.s027
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10.1371/journal.pbio.3001015.s028
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10.1371/journal.pbio.3001015.s029
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10.1371/journal.pbio.3001015.s030
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10.1371/journal.pbio.3001015.s031
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10.1371/journal.pbio.3001015.s032
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10.1371/journal.pbio.3001015.s033
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10.1371/journal.pbio.3001015.s034
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10.1371/journal.pbio.3001015.s035
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10.1371/journal.pbio.3001015.s036
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10.1371/journal.pbio.3001015.s037
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10.1371/journal.pbio.3001015.s038
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10.1371/journal.pbio.3001015.s039
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10.1371/journal.pbio.3001015.s040
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10.1371/journal.pbio.3001015.s041
DOI:
10.1371/journal.pbio.3001015.s042
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10.1371/journal.pbio.3001015.s043
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10.1371/journal.pbio.3001015.s044
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10.1371/journal.pbio.3001015.s045
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10.1371/journal.pbio.3001015.s046
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10.1371/journal.pbio.3001015.s047
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10.1371/journal.pbio.3001015.s048
DOI:
10.1371/journal.pbio.3001015.s049
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2020
detail.hit.zdb_id:
2126773-X
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