8PIE

Crystal structure of the human nucleoside diphosphate kinase B domain in complex with the product AT-8500 formed by catalysis of compound AT-9010

8PIE の概要

• エントリーDOI: 10.2210/pdb8pie/pdb
• 分子名称: Nucleoside diphosphate kinase B, [(2~{R},3~{R},4~{R},5~{R})-5-(2-azanyl-6-oxidanylidene-1~{H}-purin-9-yl)-4-fluoranyl-4-methyl-3-oxidanyl-oxolan-2-yl]methyl phosphono hydrogen phosphate, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 120130.84

構造登録者

Feracci, M.,Chazot, A.,Ferron, F.,Alvarez, K.,Canard, B. (登録日: 2023-06-21, 公開日: 2024-07-31, 最終更新日: 2024-09-04)

主引用文献

Chazot, A.,Zimberger, C.,Feracci, M.,Moussa, A.,Good, S.,Sommadossi, J.P.,Alvarez, K.,Ferron, F.,Canard, B.
The activation cascade of the broad-spectrum antiviral bemnifosbuvir characterized at atomic resolution.
Plos Biol., 22:e3002743-e3002743, 2024

PubMed Abstract: Bemnifosbuvir (AT-527) and AT-752 are guanosine analogues currently in clinical trials against several RNA viruses. Here, we show that these drugs require a minimal set of 5 cellular enzymes for activation to their common 5'-triphosphate AT-9010, with an obligate order of reactions. AT-9010 selectively inhibits essential viral enzymes, accounting for antiviral potency. Functional and structural data at atomic resolution decipher N6-purine deamination compatible with its metabolic activation. Crystal structures of human histidine triad nucleotide binding protein 1, adenosine deaminase-like protein 1, guanylate kinase 1, and nucleoside diphosphate kinase at 2.09, 2.44, 1.76, and 1.9 Å resolution, respectively, with cognate precursors of AT-9010 illuminate the activation pathway from the orally available bemnifosbuvir to AT-9010, pointing to key drug-protein contacts along the activation pathway. Our work provides a framework to integrate the design of antiviral nucleotide analogues, confronting requirements and constraints associated with activation enzymes along the 5'-triphosphate assembly line.

PubMed: 39190717
DOI: 10.1371/journal.pbio.3002743

実験手法

X-RAY DIFFRACTION (1.9 Å)