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Journal of Virology, October 2002, p. 10015-10019, Vol. 76, No. 19
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.19.10015-10019.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Crystal Structures of Zidovudine- or Lamivudine-Resistant Human Immunodeficiency Virus Type 1 Reverse Transcriptases Containing Mutations at Codons 41, 184, and 215

P. P. Chamberlain,1,2 J. Ren,1 C. E. Nichols,1,2 L. Douglas,1 J. Lennerstrand,3,{dagger} B. A. Larder,3 D. I. Stuart,1,2 and D. K. Stammers1,2*

Division of Structural Biology, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN,1 Oxford Centre for Molecular Sciences, Oxford OX1 3QT,2 Visible Genetics, Cambridge CB4 0GA, United Kingdom3

Received 25 March 2002/ Accepted 30 June 2002

Six structures of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) containing combinations of resistance mutations for zidovudine (AZT) (M41L and T215Y) or lamivudine (M184V) have been determined as inhibitor complexes. Minimal conformational changes in the polymerase or nonnucleoside RT inhibitor sites compared to the mutant RTMC (D67N, K70R, T215F, and K219N) are observed, indicating that such changes may occur only with certain combinations of mutations. Model building M41L and T215Y into HIV-1 RT-DNA and docking in ATP that is utilized in the pyrophosphorolysis reaction for AZT resistance indicates that some conformational rearrangement appears necessary in RT for ATP to interact simultaneously with the M41L and T215Y mutations.

* Corresponding author. Mailing address: Division of Structural Biology, The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom. Phone: 44-1865-287-565. Fax: 44-1865-287-547. E-mail: daves{at}strubi.ox.ac.uk.

{dagger} Present address: Division of Clinical Virology, Karolinska Institute F68, Huddinge University Hospital, S-141 86 Huddinge, Sweden.

Journal of Virology, October 2002, p. 10015-10019, Vol. 76, No. 19
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.19.10015-10019.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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