Structures of HIV-1 reverse transcriptase with pre- and post-translocation AZTMP-terminated DNA

Stefan G Sarafianos; Arthur D Clark; Kalyan Das; Steve Tuske; Jens J Birktoft; Palanichamy Ilankumaran; Andagar R Ramesha; Jane M Sayer; Donald M Jerina; Paul L Boyer; Stephen H Hughes; Eddy Arnold

doi:10.1093/emboj/cdf637

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Structures of HIV-1 reverse transcriptase with pre- and post-translocation AZTMP-terminated DNA

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Structures of HIV-1 reverse transcriptase with pre- and post-translocation AZTMP-terminated DNA

Stefan G Sarafianos, Arthur D Clark, Kalyan Das, Steve Tuske, Jens J Birktoft, Palanichamy Ilankumaran, Andagar R Ramesha, Jane M Sayer, Donald M Jerina, Paul L Boyer, …

The EMBO journal, Vol.21(23), pp.6614-6624

12/02/2002

DOI: https://doi.org/10.1093/emboj/cdf637

PMCID: PMC136941

PMID: 12456667

Abstract

translocation

drug resistance

HIV

reverse transcriptase

nucleotide excision

AZT (3′-azido-3′-deoxythymidine) resistance involves the enhanced excision of AZTMP from the end of the primer strand by HIV-1 reverse transcriptase. This reaction can occur when an AZTMP-terminated primer is bound at the n ucleotide-binding site (pre-translocation complex N) but not at the ‘ p riming’ site (post-translocation complex P). We determined the crystal structures of N and P complexes at 3.0 and 3.1 Å resolution. These structures provide insight into the structural basis of AZTMP excision and the mechanism of translocation. Docking of a dNTP in the P complex structure suggests steric crowding in forming a stable ternary complex that should increase the relative amount of the N complex, which is the substrate for excision. Structural differences between complexes N and P suggest that the conserved YMDD loop is involved in translocation, acting as a springboard that helps to propel the primer terminus from the N to the P site after dNMP incorporation.

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Title: Structures of HIV-1 reverse transcriptase with pre- and post-translocation AZTMP-terminated DNA
Creators: Stefan G Sarafianos - Center for Advanced Biotechnology and Medicine (CABM) and Rutgers University Department of Chemistry and Chemical Biology, 679 Hoes Lane, Piscataway, NJ 08854-5638
Arthur D Clark - Center for Advanced Biotechnology and Medicine (CABM) and Rutgers University Department of Chemistry and Chemical Biology, 679 Hoes Lane, Piscataway, NJ 08854-5638
Kalyan Das - Center for Advanced Biotechnology and Medicine (CABM) and Rutgers University Department of Chemistry and Chemical Biology, 679 Hoes Lane, Piscataway, NJ 08854-5638
Steve Tuske - Center for Advanced Biotechnology and Medicine (CABM) and Rutgers University Department of Chemistry and Chemical Biology, 679 Hoes Lane, Piscataway, NJ 08854-5638
Jens J Birktoft - Center for Advanced Biotechnology and Medicine (CABM) and Rutgers University Department of Chemistry and Chemical Biology, 679 Hoes Lane, Piscataway, NJ 08854-5638
Palanichamy Ilankumaran - Center for Advanced Biotechnology and Medicine (CABM) and Rutgers University Department of Chemistry and Chemical Biology, 679 Hoes Lane, Piscataway, NJ 08854-5638
Andagar R Ramesha - Center for Advanced Biotechnology and Medicine (CABM) and Rutgers University Department of Chemistry and Chemical Biology, 679 Hoes Lane, Piscataway, NJ 08854-5638
Jane M Sayer - Center for Advanced Biotechnology and Medicine (CABM) and Rutgers University Department of Chemistry and Chemical Biology, 679 Hoes Lane, Piscataway, NJ 08854-5638
Donald M Jerina - Center for Advanced Biotechnology and Medicine (CABM) and Rutgers University Department of Chemistry and Chemical Biology, 679 Hoes Lane, Piscataway, NJ 08854-5638
Paul L Boyer - Center for Advanced Biotechnology and Medicine (CABM) and Rutgers University Department of Chemistry and Chemical Biology, 679 Hoes Lane, Piscataway, NJ 08854-5638
Stephen H Hughes - Center for Advanced Biotechnology and Medicine (CABM) and Rutgers University Department of Chemistry and Chemical Biology, 679 Hoes Lane, Piscataway, NJ 08854-5638
Eddy Arnold - Center for Advanced Biotechnology and Medicine (CABM) and Rutgers University Department of Chemistry and Chemical Biology, 679 Hoes Lane, Piscataway, NJ 08854-5638
Publication Details: The EMBO journal, Vol.21(23), pp.6614-6624
Date published: 12/02/2002
Publisher: Oxford University Press
Academic Unit: Center for Advanced Biotechnology and Medicine
Language: English
Resource Type: Journal article
Identifiers: 991031654928504646