Aphidicolin resistance in herpes simplex virus type I reveals features of the DNA polymerase dNTP binding site.
Aphidicolin resistance in herpes simplex virus type I reveals features of the DNA polymerase dNTP binding site.
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DOI：
10.1093/nar/17.22.9231
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发表时间：
1989-11
影响因子：
14.9
通讯作者：
J. Hall;Y. S. Wang;J. Pierpont;M. Berlin;S. Rundlett;S. Woodward
中科院分区：
文献类型：
--
作者：
J. Hall;Y. S. Wang;J. Pierpont;M. Berlin;S. Rundlett;S. Woodward
我们描述了单纯疱疹病毒1型DNA聚合酶基因内的突变的映射和测序，该基因赋予对DNA聚合酶抑制剂阿非迪霉素的抗性。突变发生在与单纯疱疹病毒相关的DNA聚合酶中高度保守的两个区域附近。它们也发生在其他单纯疱疹病毒突变附近，这些突变影响聚合酶和脱氧核苷三磷酸底物之间的相互作用。因此，我们主张赞成的想法，即阿非迪霉素结合位点重叠的底物结合位点和附近的保守区域的功能所需的底物结合。我们的突变体还表现出对另一种DNA聚合酶抑制剂膦酰乙酸的异常敏感性。这种药物被认为是焦磷酸盐的类似物。第二个网站的突变，抑制一个突变体的超敏反应膦酰乙酸（但不是其aphidicolin耐药性）的描述。这第二个突变可能代表了一类新的突变，它特异性地影响焦磷酸，但不影响底物结合。
We describe the mapping and sequencing of mutations within the DNA polymerase gene of herpes simplex virus type 1 which confer resistance to aphidicolin, a DNA polymerase inhibitor. The mutations occur near two regions which are highly conserved among DNA polymerases related to the herpes simplex enzyme. They also occur near other herpes simplex mutations which affect the interactions between the polymerase and deoxyribonucleoside triphosphate substrates. Consequently, we argue in favor of the idea that the aphidicolin binding site overlaps the substrate binding site and that the near-by conserved regions are functionally required for substrate binding. Our mutants also exhibit abnormal sensitivity to another DNA polymerase inhibitor, phosphonoacetic acid. This drug is thought to bind as an analogue of pyrophosphate. A second-site mutation which suppresses the hypersensitivity of one mutant to phosphonoacetic acid (but not its aphidicolin resistance) is described. This second mutation may represent a new class of mutations, which specifically affects pyrophosphate, but not substrate, binding.