Jacques, DA;
McEwan, WA;
Hilditch, L;
Price, AJ;
Towers, GJ;
James, LC;
(2016)
HIV-1 uses dynamic capsid pores to import nucleotides and fuel encapsidated DNA synthesis.
Nature
, 536
(7616)
pp. 349-353.
10.1038/nature19098.
Preview |
Text
Towers_Jacques_etal_Revised_FigsIncluded.pdf - Accepted Version Download (8MB) | Preview |
Abstract
During the early stages of infection, the HIV-1 capsid protects viral components from cytosolic sensors and nucleases such as cGAS and TREX, respectively, while allowing access to nucleotides for efficient reverse transcription1 . Here we show that each capsid hexamer has a size-selective pore bound by a ring of six arginine residues and a ‘molecular iris’ formed by the amino-terminal β-hairpin. The arginine ring creates a strongly positively charged channel that recruits the four nucleotides with on-rates that approach diffusion limits. Progressive removal of pore arginines results in a dose-dependent and concomitant decrease in nucleotide affinity, reverse transcription and infectivity. This positively charged channel is universally conserved in lentiviral capsids despite the fact that it is strongly destabilizing without nucleotides to counteract charge repulsion. We also describe a channel inhibitor, hexacarboxybenzene, which competes for nucleotide binding and efficiently blocks encapsidated reverse transcription, demonstrating the tractability of the pore as a novel drug target.
Type: | Article |
---|---|
Title: | HIV-1 uses dynamic capsid pores to import nucleotides and fuel encapsidated DNA synthesis |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.1038/nature19098 |
Publisher version: | http://doi.org/10.1038/nature19098 |
Language: | English |
Additional information: | © 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. |
Keywords: | Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, AMINO-TERMINAL DOMAIN, CRYSTAL-STRUCTURES, PROTEIN, RECOGNITION |
UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity |
URI: | https://discovery.ucl.ac.uk/id/eprint/1528171 |
Archive Staff Only
View Item |