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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
10
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pubmed:dateCreated |
2010-10-6
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pubmed:databankReference |
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pubmed:abstractText |
Human immunodeficiency virus (HIV-1) develops resistance to 3'-azido-2',3'-deoxythymidine (AZT, zidovudine) by acquiring mutations in reverse transcriptase that enhance the ATP-mediated excision of AZT monophosphate from the 3' end of the primer. The excision reaction occurs at the dNTP-binding site, uses ATP as a pyrophosphate donor, unblocks the primer terminus and allows reverse transcriptase to continue viral DNA synthesis. The excision product is AZT adenosine dinucleoside tetraphosphate (AZTppppA). We determined five crystal structures: wild-type reverse transcriptase-double-stranded DNA (RT-dsDNA)-AZTppppA; AZT-resistant (AZTr; M41L D67N K70R T215Y K219Q) RT-dsDNA-AZTppppA; AZTr RT-dsDNA terminated with AZT at dNTP- and primer-binding sites; and AZTr apo reverse transcriptase. The AMP part of AZTppppA bound differently to wild-type and AZTr reverse transcriptases, whereas the AZT triphosphate part bound the two enzymes similarly. Thus, the resistance mutations create a high-affinity ATP-binding site. The structure of the site provides an opportunity to design inhibitors of AZT-monophosphate excision.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/3'-azido-3'-deoxythymidine...,
http://linkedlifedata.com/resource/pubmed/chemical/AZTp4A,
http://linkedlifedata.com/resource/pubmed/chemical/Adenosine Triphosphate,
http://linkedlifedata.com/resource/pubmed/chemical/DNA, Viral,
http://linkedlifedata.com/resource/pubmed/chemical/Deoxyribonucleotides,
http://linkedlifedata.com/resource/pubmed/chemical/Dideoxynucleotides,
http://linkedlifedata.com/resource/pubmed/chemical/HIV Reverse Transcriptase,
http://linkedlifedata.com/resource/pubmed/chemical/Reverse Transcriptase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Thymine Nucleotides,
http://linkedlifedata.com/resource/pubmed/chemical/Zidovudine,
http://linkedlifedata.com/resource/pubmed/chemical/reverse transcriptase, Human...
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pubmed:status |
MEDLINE
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pubmed:month |
Oct
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pubmed:issn |
1545-9985
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pubmed:author |
pubmed-author:ArnoldEddyE,
pubmed-author:BaumanJoseph DJD,
pubmed-author:BoyerPaul LPL,
pubmed-author:ClarkArthur DADJr,
pubmed-author:DasKalyanK,
pubmed-author:FrenkelYulia VYV,
pubmed-author:GaffneyBarbara LBL,
pubmed-author:HanQianweiQ,
pubmed-author:HouXiaorongX,
pubmed-author:HughesStephen HSH,
pubmed-author:JonesRoger ARA,
pubmed-author:SarafianosStefan GSG,
pubmed-author:TuXiongyingX
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pubmed:issnType |
Electronic
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pubmed:volume |
17
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1202-9
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pubmed:dateRevised |
2010-12-3
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pubmed:meshHeading |
pubmed-meshheading:20852643-Adenosine Triphosphate,
pubmed-meshheading:20852643-Amino Acid Substitution,
pubmed-meshheading:20852643-Binding Sites,
pubmed-meshheading:20852643-Crystallography, X-Ray,
pubmed-meshheading:20852643-DNA, Viral,
pubmed-meshheading:20852643-Deoxyribonucleotides,
pubmed-meshheading:20852643-Dideoxynucleotides,
pubmed-meshheading:20852643-Drug Design,
pubmed-meshheading:20852643-Drug Resistance, Viral,
pubmed-meshheading:20852643-Genes, rev,
pubmed-meshheading:20852643-HIV Reverse Transcriptase,
pubmed-meshheading:20852643-HIV-1,
pubmed-meshheading:20852643-Models, Molecular,
pubmed-meshheading:20852643-Mutation, Missense,
pubmed-meshheading:20852643-Point Mutation,
pubmed-meshheading:20852643-Protein Conformation,
pubmed-meshheading:20852643-Reverse Transcriptase Inhibitors,
pubmed-meshheading:20852643-Structure-Activity Relationship,
pubmed-meshheading:20852643-Thymine Nucleotides,
pubmed-meshheading:20852643-Zidovudine
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pubmed:year |
2010
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pubmed:articleTitle |
Structural basis of HIV-1 resistance to AZT by excision.
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pubmed:affiliation |
Center for Advanced Biotechnology and Medicine, Piscataway, New Jersey, USA.
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pubmed:publicationType |
Journal Article
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