最近，得克薩斯大學(xué)的研究人員發(fā)現(xiàn)了一種重要的酶的原子結(jié)構(gòu),，這項(xiàng)發(fā)現(xiàn)發(fā)表在本周的Cell雜志上,，或許對開發(fā)低副作用的抗HIV的藥物有重要的影響。
據(jù)研究人員Whitney Yin介紹,，當(dāng)前許多抗HIV藥物基本是以阻止DNA的復(fù)制過程為主,，雖然這對阻止病毒感染很有效，但該類藥物同時也阻止了人體細(xì)胞中具有相似功能的酶功能的發(fā)揮,，因此,，對人體有較大的副反應(yīng)。
人類細(xì)胞中負(fù)責(zé)DNA復(fù)制的酶為Pol γ,，當(dāng)Pol γ接觸到上述抗病毒藥物時,，藥物干擾DNA復(fù)制過程，從而破壞線粒體的功能,，引起惡心,、骨髓耗盡、器官衰竭等各種副反應(yīng),。Yin介紹說,，服用這類藥物的HIV患者長期承受藥物的毒性反應(yīng)，雖然科學(xué)家已知Pol γ能夠調(diào)解這類藥物的毒性,，但是在不了解Pol γ結(jié)構(gòu)的情況下，設(shè)計(jì)一種能夠完全區(qū)別開HIV和Pol γ的藥物還是有很大的困難,。
在該研究中,，Yin等人通過實(shí)驗(yàn)獲得Pol γ的原子結(jié)構(gòu)。在已知Pol γ和HIV結(jié)構(gòu)的條件下,，研究人員可以利用二者結(jié)構(gòu)上的差異開發(fā)出更多可供選擇的藥物,，從而選擇出毒性更低的抗HIV的藥物,。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
