CRYSTAL-STRUCTURE AT 3.5 ANGSTROM RESOLUTION OF HIV-1 REVERSE-TRANSCRIPTASE COMPLEXED WITH AN INHIBITOR
CRYSTAL-STRUCTURE AT 3.5 ANGSTROM RESOLUTION OF HIV-1 REVERSE-TRANSCRIPTASE COMPLEXED WITH AN INHIBITOR
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DOI：
10.1126/science.1377403
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发表时间：
1992-06-26
期刊：
影响因子：
56.9
通讯作者：
STEITZ, TA
中科院分区：
文献类型：
--
作者：
KOHLSTAEDT, LA;WANG, J;STEITZ, TA
HIV-1逆转录酶异源二聚体与奈韦拉平（一种具有治疗艾滋病潜力的药物）复合的3.5埃分辨率电子密度图显示为不对称二聚体。66千道尔顿亚基的聚合酶（pol）结构域有一个类似于大肠杆菌DNA聚合酶I的Klenow片段的大裂缝。然而，相同序列的51千道尔顿亚基没有这样的裂缝，因为pol结构域的四个亚结构域占据完全不同的相对位置。四个波尔亚结构域中的两个似乎与Klenow片段的亚结构域在结构上相关，包括一个含有催化位点的亚结构域。在两种聚合酶中，似乎可能在pol活性位点结合模板链的亚结构域具有不同的结构。双链体A形式的RNA-DNA杂交体可以模型构建到核糖核酸酶H和pol活性位点之间的裂缝中。奈韦拉平几乎完全埋在pol活性位点附近但不与pol活性位点重叠的口袋中。已大致定位了突变导致耐药性的残基。
A 3.5 angstrom resolution electron density map of the HIV-1 reverse transcriptase heterodimer complexed with nevirapine, a drug with potential for treatment of AIDS, reveals an asymmetric dimer. The polymerase (pol) domain of the 66-kilodalton subunit has a large cleft analogous to that of the Klenow fragment of Escherichia coli DNA polymerase I. However, the 51-kilodalton subunit of identical sequence has no such cleft because the four subdomains of the pol domain occupy completely different relative positions. Two of the four pol subdomains appear to be structurally related to subdomains of the Klenow fragment, including one containing the catalytic site. The subdomain that appears likely to bind the template strand at the pol active site has a different structure in the two polymerases. Duplex A-form RNA-DNA hybrid can be model-built into the cleft that runs between the ribonuclease H and pol active sites. Nevirapine is almost completely buried in a pocket near but not overlapping with the pol active site. Residues whose mutation results in drug resistance have been approximately located.