8PWK

human HINT1 in complex with compound AT8003

Summary for 8PWK

• Entry DOI: 10.2210/pdb8pwk/pdb
• Descriptor: Histidine triad nucleotide-binding protein 1, [(2~{R},3~{R},4~{R},5~{R})-5-[2-azanyl-6-(methylamino)purin-9-yl]-4-fluoranyl-4-methyl-3-oxidanyl-oxolan-2-yl]methyl dihydrogen phosphate, SODIUM ION, ... (4 entities in total)
• Functional Keywords: complex intermediate compound inhibitor, adenosine 5'-monophosphoramidase, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 28063.13

Authors

Zimberger, C.,Canard, B.,Ferron, F. (deposition date: 2023-07-20, release date: 2024-07-31, Last modification date: 2024-09-04)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.095 Å)