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Structures of Wild‐Type and AZT‐Resistant HIV‐1 Reverse Transcriptase Complexed with AZTppppA Yield Insights into the Nucleotide Excision Mechanism
Author(s) -
Tu Xiongying,
Sarafianos Stefan G,
Han Qianwei,
Das Kalyan,
Hou Xiaorong,
Bauman Joe,
Clark Arthur D,
Gaffney Babara L,
Jones Roger A,
Boyer Paul L,
Hughes Stephen H,
Arnold Eddy
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a640-a
Subject(s) - reverse transcriptase , moiety , nucleotide , dna , wild type , chemistry , mutation , mutant , nucleoside , zidovudine , virology , biology , microbiology and biotechnology , stereochemistry , human immunodeficiency virus (hiv) , biochemistry , polymerase chain reaction , gene , viral disease
AZT, 3′‐azido‐3′‐deoxythymidine, is an important anti‐AIDS drug. HIV‐1 can develop resistance to AZT and other nucleoside analogs by an excision mechanism that unblocks chain‐terminated primers. The product of the excision reaction is a dinucleoside tetraphosphate (AZTppppA). The structural details of the excision mechanism have not been elucidated. We have solved the crystal structures of wild‐type (3.1 Å) and AZT‐resistant (3.2 Å) HIV‐1 RT cross‐linked to DNA in complex with AZTppppA. The structures reveal that the ATP moiety binds differently to AZT‐resistant and wild‐type RT. In the AZT‐resistant RT‐DNA/AZTppppA complex, the adenine moiety has π–π stacking interactions with T215Y. The other AZT‐resistant mutations M41L, D67N, K70R and K219Q interact directly or indirectly with the ATP. None of these interactions are observed in the wild‐type HIV‐1 RT‐DNA/AZTppppA complex structure. These data show that AZT‐resistance mutations enhance excision by optimizing ATP binding and positioning, and also provide hints for drug design.