7V3C

Crystal structure of NP exonuclease C409A-PCMB complex

7V3C の概要

• エントリーDOI: 10.2210/pdb7v3c/pdb
• 関連するPDBエントリー: 7V37 7V38 7V39 7V3A 7V3B
• 分子名称: Nucleoprotein, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: deddh exonuclease, np exonuclease, anti-viral drug, pcmps, pcmb, viral protein
• 由来する生物種: Lassa virus (strain Mouse/Sierra Leone/Josiah/1976) (LASV)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 55841.29

構造登録者

Hsiao, Y.Y.,Huang, K.W. (登録日: 2021-08-10, 公開日: 2021-12-15, 最終更新日: 2023-11-29)

主引用文献

Huang, K.W.,Chen, J.W.,Hua, T.Y.,Chu, Y.Y.,Chiu, T.Y.,Liu, J.Y.,Tu, C.I.,Hsu, K.C.,Kao, Y.T.,Chu, J.W.,Hsiao, Y.Y.
Targeted Covalent Inhibitors Allosterically Deactivate the DEDDh Lassa Fever Virus NP Exonuclease from Alternative Distal Sites.
Jacs Au, 1:2315-2327, 2021

PubMed Abstract: For using targeted covalent inhibitors (TCIs) as anticancer and antiviral drugs, we establish that the model compounds PCMPS (-chloromercuriphenyl sulfate) and PCMB (-chloromercuribenzoate) are inhibitors of the DEDDh family of exonucleases. The underlying mechanism is analyzed by X-ray crystallography, activity/nucleic acid-binding assays, and all-atom molecular dynamics (MD) simulations. The first TCI-complexed structures of a DEDDh enzyme, the Lassa fever virus NP exonuclease (NPexo), are resolved to elucidate that the Cys409 binding site is away from the active site and the RNA-binding lid. The NPexo C409A structures indicate Cys461 as the alternative distal site for obstructing the equally active mutant. All-atom MD simulations of the wild type and mutant NPexos in explicit solvent uncover an allosteric inhibition mechanism that the local perturbation induced by PCMPS sulfonate propagates to impact the RNA-binding lid conformation. Binding assay studies confirm that PCMPS does affect the RNA binding of NPexo. The predicted relative potency between PCMPS and PCMB is also in line with experiments. The structural data and inhibition mechanism established in this work provide an important molecular basis for the drug development of TCIs.

PubMed: 34977900
DOI: 10.1021/jacsau.1c00420

実験手法

X-RAY DIFFRACTION (1.9 Å)