研究发现线粒体DNA复制酶结构

　　得克萨斯大学的研究人员发现了一种重要的酶的原子结构，这项发现发表在Cell杂志上，或许对开发低副作用的抗HIV的药物有重要的影响。

　　据研究人员Whitney Yin介绍，当前许多抗HIV药物基本是以阻止DNA的复制过程为主，虽然这对阻止病毒感染很有效，但该类药物同时也阻止了人体细胞中具有相似功能的酶功能的发挥，因此，对人体有较大的副反应。

　　人类细胞中负责DNA复制的酶为Pol γ，当Pol γ接触到上述抗病毒药物时，药物干扰DNA复制过程，从而破坏线粒体的功能，引起恶心、骨髓耗尽、器官衰竭等各种副反应。Yin介绍说，服用这类药物的HIV患者长期承受药物的毒性反应，虽然科学家已知Pol γ能够调解这类药物的毒性，但是在不了解Pol γ结构的情况下，设计一种能够完全区别开HIV和Pol γ的药物还是有很大的困难。

　　在该研究中，Yin等人通过实验获得Pol γ的原子结构。在已知Pol γ和HIV结构的条件下，研究人员可以利用二者结构上的差异开发出更多可供选择的药物，从而选择出毒性更低的抗HIV的药物。

Cell, Volume 139,16 October 2009 doi:10.1016/j.cell.2009.07.050

Structural Insight into Processive Human Mitochondrial DNA Synthesis and Disease-Related Polymerase Mutations

Young-Sam Lee1, W. Dexter Kennedy1 and Y. Whitney Yin1, 2, ,

1 Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA
2 Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, TX 78712, USA

Human mitochondrial DNA polymerase (Pol γ) is the sole replicase in mitochondria. Pol γ is vulnerable to nonselective antiretroviral drugs and is increasingly associated with mutations found in patients with mitochondriopathies. We determined crystal structures of the human heterotrimeric Pol γ holoenzyme and, separately, a variant of its processivity factor, Pol γB. The holoenzyme structure reveals an unexpected assembly of the mitochondrial DNA replicase where the catalytic subunit Pol γA interacts with its processivity factor primarily via a domain that is absent in all other DNA polymerases. This domain provides a structural module for supporting both the intrinsic processivity of the catalytic subunit alone and the enhanced processivity of holoenzyme. The Pol γ structure also provides a context for interpreting the phenotypes of disease-related mutations in the polymerase and establishes a foundation for understanding the molecular basis of toxicity of anti-retroviral drugs targeting HIV reverse transcriptase.