EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	Viral DNA polymerase structures reveal mechanisms of antiviral drug resistance.
ジャーナル・号・ページ	Cell, Vol. 187, Issue 20, Page 5572-5586.e15, Year 2024
掲載日	2024年10月3日
著者	Sundaresh Shankar / Junhua Pan / Pan Yang / Yuemin Bian / Gábor Oroszlán / Zishuo Yu / Purba Mukherjee / David J Filman / James M Hogle / Mrinal Shekhar / Donald M Coen / Jonathan Abraham /
PubMed 要旨	DNA polymerases are important drug targets, and many structural studies have captured them in distinct conformations. However, a detailed understanding of the impact of polymerase conformational ...DNA polymerases are important drug targets, and many structural studies have captured them in distinct conformations. However, a detailed understanding of the impact of polymerase conformational dynamics on drug resistance is lacking. We determined cryoelectron microscopy (cryo-EM) structures of DNA-bound herpes simplex virus polymerase holoenzyme in multiple conformations and interacting with antivirals in clinical use. These structures reveal how the catalytic subunit Pol and the processivity factor UL42 bind DNA to promote processive DNA synthesis. Unexpectedly, in the absence of an incoming nucleotide, we observed Pol in multiple conformations with the closed state sampled by the fingers domain. Drug-bound structures reveal how antivirals may selectively bind enzymes that more readily adopt the closed conformation. Molecular dynamics simulations and the cryo-EM structure of a drug-resistant mutant indicate that some resistance mutations modulate conformational dynamics rather than directly impacting drug binding, thus clarifying mechanisms that drive drug selectivity.
リンク	Cell / PubMed:39197451
手法	EM (単粒子)
解像度	2.7 - 5.1 Å
構造データ	28663 8exx EMDB-28663, PDB-8exx: Herpes simplex virus 1 polymerase holoenzyme bound to DNA and foscarnet (pre-translocation state) 手法: EM (単粒子) / 解像度: 3.3 Å EMDB-28664: Herpes simplex virus 1 DNA polymerase holoenzyme bound to DNA template and primer, dNTP-free (editing mode) 手法: EM (単粒子) / 解像度: 3.77 Å 42887 8v1q EMDB-42887, PDB-8v1q: Herpes simplex virus 1 polymerase holoenzyme bound to DNA in both open/closed conformations 手法: EM (単粒子) / 解像度: 2.7 Å 42888 8v1r EMDB-42888, PDB-8v1r: Herpes simplex virus 1 polymerase holoenzyme bound to DNA and DTTP in closed conformation 手法: EM (単粒子) / 解像度: 2.9 Å 42889 8v1s EMDB-42889, PDB-8v1s: Herpes simplex virus 1 polymerase holoenzyme bound to mismatched DNA in editing conformation 手法: EM (単粒子) / 解像度: 3.26 Å 42890 8v1t EMDB-42890, PDB-8v1t: Herpes simplex virus 1 polymerase holoenzyme bound to DNA and acyclovir triphosphate in closed conformation 手法: EM (単粒子) / 解像度: 2.8 Å EMDB-42891: Herpes simplex virus 1 polymerase W781V mutant holoenzyme bound to DNA in editing conformation 手法: EM (単粒子) / 解像度: 5.1 Å
化合物	ChemComp-MG: Unknown entry / マグネシウムジカチオン ChemComp-PPF: PHOSPHONOFORMIC ACID / ホスカルネット / 薬剤, 抗ウイルス剤, 阻害剤YM ChemComp-HOH: WATER ChemComp-TTP: THYMIDINE-5'-TRIPHOSPHATE / dTTP ChemComp-AVP*: ACYCLOVIR TRIPHOSPHATE / アシクロビルトリホスファ-ト
由来	Human herpesvirus 1 (strain KOS) (ヘルペスウイルス) human alphaherpesvirus 1 strain kos (ヘルペスウイルス) synthetic construct (人工物)
キーワード	VIRAL PROTEIN/DNA / herpes simplex virus / replication / DNA polymerase holoenzyme / UL30 / UL42 / pre-translocation / foscarnet / VIRAL PROTEIN / VIRAL PROTEIN-DNA complex / TRANSFERASE/DNA / open/closed conformations / conformational dynamics / TRANSFERASE-DNA complex / closed conformation / editing conformation / DNA polymerase / ACYCLOVIR / antiherpesvirus drug