Structures of DNA Polymerase Mispaired DNA Termini Transitioning to Pre-catalytic Complexes Support an Induced-Fit Fidelity Mechanism.
Structures of DNA Polymerase Mispaired DNA Termini Transitioning to Pre-catalytic Complexes Support an Induced-Fit Fidelity Mechanism.
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DOI：
10.1016/j.str.2016.08.006
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发表时间：
2016-11-01
期刊：
影响因子：
5.7
通讯作者：
Wilson, Samuel H.
中科院分区：
文献类型：
--
作者：
Batra, Vinod K.;Beard, William A.;Pedersen, Lars C.;Wilson, Samuel H.
高保真DNA合成要求聚合酶对正确的核苷酸插入表现出强烈的偏好。当插入错误的核苷酸时，聚合酶阻止从错配的DNA末端延伸。确定了23种末端模板-引物错配的DNA聚合酶β的晶体学结构为二元DNA和三元预催化底物复合物。这些结构表明，不匹配的终端采取各种扭曲的构象，试图满足堆叠和氢键相互作用。二元复合物结构表明在错配的模板核苷酸中诱导的应变。添加不可水解的引入核苷酸使模板核苷酸与引物末端中的伴随菌株稳定。几个死端三元复合物结构表明，DNA合成可能发生的酶从开放到封闭的复合物的过渡。这些结构与诱导配合机制一致，其中错配的末端相对于正确的进入核苷酸错配，以阻止或延迟进一步的DNA合成。
High fidelity DNA synthesis requires that polymerases display a strong preference for right nucleotide insertion. When the wrong nucleotide is inserted, the polymerase deters extension from the mismatched DNA terminus. Twenty-three crystallographic structures of DNA polymerase β with terminal template-primer mismatches were determined as binary DNA and ternary pre-catalytic substrate complexes. These structures indicate that the mismatched termini adopt various distorted conformations that attempt to satisfy stacking and hydrogen bonding interactions. The binary complex structures indicate an induced strain in the mismatched template nucleotide. Addition of a non-hydrolysable incoming nucleotide stabilizes the templating nucleotide with concomitant strain in the primer terminus. Several dead-end ternary complex structures suggest that DNA synthesis might occur as the enzyme transitions from an open to closed complex. The structures are consistent with an induced fit mechanism where a mismatched terminus is misaligned relative to the correct incoming nucleotide to deter or delay further DNA synthesis.
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