Detecting allosteric sites of HIV-1 reverse transcriptase by X-ray crystallographic fragment screening.
Detecting allosteric sites of HIV-1 reverse transcriptase by X-ray crystallographic fragment screening.
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DOI：
10.1021/jm301271j
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发表时间：
2013-04-11
影响因子：
7.3
通讯作者：
Arnold, Eddy
中科院分区：
文献类型：
--
作者：
Bauman, Joseph D.;Patel, Disha;Dharia, Chhaya;Fromer, Marc W.;Ahmed, Sameer;Frenkel, Yulia;Vijayan, R. S. K.;Eck, J. Thomas;Ho, William C.;Das, Kalyan;Shatkin, Aaron J.;Arnold, Eddy
HIV-1逆转录酶（RT）在病毒复制过程中经历一系列构象变化，是抗逆转录病毒治疗的中心靶点。RT的内在灵活性可以提供新的抑制变构位点。将X射线衍射至优于2 μ m分辨率的RT晶体促进了通过X射线晶体学使用片段筛选来探测RT以寻找新的可药用位点。将总共775个片段分组为143个混合物，将其浸泡在与非核苷药物利匹韦林（TMC 278）复合的RT晶体中。发现了7个新位点，包括位于RT聚合酶区域的Incoming Nucleotide Binding、Knuckles、NNRTI Adjacent和399位点，以及位于RNase H区域的428、RNase H Primer Grip Adjacent和507位点。其中三个位点--指关节、NNRTI邻近位点和传入核苷酸结合位点--具有抑制作用，并为发现新的抗艾滋病药物提供了机会。
HIV-1 reverse transcriptase (RT) undergoes a series of conformational changes during viral replication and is a central target for antiretroviral therapy. The intrinsic flexibility of RT can provide novel allosteric sites for inhibition. Crystals of RT that diffract X-rays to better than 2 Å resolution facilitated the probing of RT for new druggable sites using fragment screening by X-ray crystallography. A total of 775 fragments were grouped into 143 cocktails, which were soaked into crystals of RT in complex with the non-nucleoside drug rilpivirine (TMC278). Seven new sites were discovered, including the Incoming Nucleotide Binding, Knuckles, NNRTI Adjacent, and 399 sites, located in the polymerase region of RT, and the 428, RNase H Primer Grip Adjacent, and 507 sites, located in the RNase H region. Three of these sites—Knuckles, NNRTI Adjacent, and Incoming Nucleotide Binding—are inhibitory and provide opportunities for discovery of new anti-AIDS drugs.
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DOI：
10.2174/1386207023329923
发表时间：
2002-12-01
影响因子：
1.8
作者：
Dalvit, C;Flocco, M;Stockman, BJ
通讯作者：
Stockman, BJ
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
DOI：
10.1107/s0907444998003254
发表时间：
1998-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Brunger, AT;Adams, PD;Warren, GL
通讯作者：
Warren, GL
DOI：
10.1107/s0907444910007493
发表时间：
2010-04
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Emsley P;Lohkamp B;Scott WG;Cowtan K
通讯作者：
Cowtan K
影响因子：
16.8
作者：
Das, Kalyan;Martinez, Sergio E.;Arnold, Eddy
通讯作者：
Arnold, Eddy