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HIV-1 uses dynamic capsid pores to import nucleotides and fuel encapsidated DNA synthesis

DOI: 10.1038/nature19098 DOI Help

Authors: David A. Jacques (MRC Laboratory of Molecular Biology) , William A. Mcewan (MRC Laboratory of Molecular Biology) , Laura Hilditch (Infection and Immunity, University College London) , Amanda J. Price (Astex Pharmaceuticals) , Greg J. Towers (Infection and Immunity, University College London) , Leo C. James (MRC Laboratory of Molecular Biology)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Nature , VOL 536 , PAGES 349 - 353

State: Published (Approved)
Published: August 2016
Diamond Proposal Number(s): 11235

Open Access Open Access

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.

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography

Added On: 20/09/2016 13:25

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nature19098.pdf

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