5C53

Probing the Structural and Molecular Basis of Nucleotide Selectivity by Human Mitochondrial DNA Polymerase gamma

5C53 の概要

• エントリーDOI: 10.2210/pdb5c53/pdb
• 関連するPDBエントリー: 5C52
• 分子名称: DNA polymerase subunit gamma-1, Pol gamma B, DNA (26-MER), ... (7 entities in total)
• 機能のキーワード: nucleoside reverse transcriptase inhibitors (nrtis), hiv reverse transcriptase (rt), human mitochondrial dna polymerase, mitochondrial toxicity, drug efficacy and toxicity, transferase, transferase-dna complex, transferase/dna
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Mitochondrion : P54098
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 356486.26

構造登録者

Sohl, C.D.,Szymanski, M.R.,Mislak, A.C.,Shumate, C.K.,Amiralaei, S.,Schinazi, R.F.,Anderson, K.S.,Yin, Y.W. (登録日: 2015-06-19, 公開日: 2016-01-27, 最終更新日: 2024-03-06)

主引用文献

Sohl, C.D.,Szymanski, M.R.,Mislak, A.C.,Shumate, C.K.,Amiralaei, S.,Schinazi, R.F.,Anderson, K.S.,Yin, Y.W.
Probing the structural and molecular basis of nucleotide selectivity by human mitochondrial DNA polymerase gamma.
Proc.Natl.Acad.Sci.USA, 112:8596-8601, 2015

PubMed Abstract: Nucleoside analog reverse transcriptase inhibitors (NRTIs) are the essential components of highly active antiretroviral (HAART) therapy targeting HIV reverse transcriptase (RT). NRTI triphosphates (NRTI-TP), the biologically active forms, act as chain terminators of viral DNA synthesis. Unfortunately, NRTIs also inhibit human mitochondrial DNA polymerase (Pol γ), causing unwanted mitochondrial toxicity. Understanding the structural and mechanistic differences between Pol γ and RT in response to NRTIs will provide invaluable insight to aid in designing more effective drugs with lower toxicity. The NRTIs emtricitabine [(-)-2,3'-dideoxy-5-fluoro-3'-thiacytidine, (-)-FTC] and lamivudine, [(-)-2,3'-dideoxy-3'-thiacytidine, (-)-3TC] are both potent RT inhibitors, but Pol γ discriminates against (-)-FTC-TP by two orders of magnitude better than (-)-3TC-TP. Furthermore, although (-)-FTC-TP is only slightly more potent against HIV RT than its enantiomer (+)-FTC-TP, it is discriminated by human Pol γ four orders of magnitude more efficiently than (+)-FTC-TP. As a result, (-)-FTC is a much less toxic NRTI. Here, we present the structural and kinetic basis for this striking difference by identifying the discriminator residues of drug selectivity in both viral and human enzymes responsible for substrate selection and inhibitor specificity. For the first time, to our knowledge, this work illuminates the mechanism of (-)-FTC-TP differential selectivity and provides a structural scaffold for development of novel NRTIs with lower toxicity.

PubMed: 26124101
DOI: 10.1073/pnas.1421733112

実験手法

X-RAY DIFFRACTION (3.567 Å)