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2.2 Å RESOLUTION STRUCTURE OF THE AMINO-TERMINAL HALF OF HIV-1 REVERSE-TRANSCRIPTASE (FINGERS AND PALM SUBDOMAINS)

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Author(s)

  • T UNGE
  • S KNIGHT
  • R BHIKHABHAI
  • S LOVGREN
  • Z DAUTER
  • K WILSON
  • B STRANDBERG

Department/unit(s)

Publication details

JournalStructure
DatePublished - 15 Oct 1994
Issue number10
Volume2
Number of pages9
Pages (from-to)953-961
Original languageEnglish

Abstract

Background: HIV-1 reverse transcriptase (RT) catalyzes the transformation of single-stranded viral RNA into double-stranded DNA, which is integrated into host cell chromosomes. The molecule is a heterodimer of two subunits, p51 and p66. The amino acid sequence of p51 is identical to the sequence of the amino-terminal subdomains of p66. Earlier crystallogaphic studies indicate that the RT molecule is flexible, which may explain the difficulty in obtaining high-resolution data for the intact protein. We have therefore determined the structure of a fragment of RT (RT216), which contains only the amino-terminal half of the RT molecule ('finger' and 'palm' subdomains).

Results: The crystal structure of RT216 has been refined at 2.2 Angstrom resolution to a crystallographic R-value of 20.8%. The structure is very similar to that of the corresponding part of the p66 subunit in the p66/p51 heterodimer, although there is a small difference in the relative orientation of the two subdomains compared with the structure of an RT-DNA-antibody fragment complex. There are a large number of stabilizing contacts (mainly hydrogen bonds and hydrophobic interactions) between the subdomains. The locations of conserved amino acids and the position of some important drug-resistant mutations are described.

Conclusions: The RT216 structure provides detailed three-dimensional information of one important part of HIV-1 RT (including the critical active site residues). We propose a model to explain the inhibitory effect of non-nucleoside inhibitors, which partially accounts for their effect in terms of conformational changes of active site residues.

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