7B69

BK Polyomavirus VP1 pentamer core(residues 26-299) mutant C104S

This is a non-PDB format compatible entry.

Summary for 7B69

• Entry DOI: 10.2210/pdb7b69/pdb
• Descriptor: Major capsid protein VP1, DIMETHYL SULFOXIDE (3 entities in total)
• Functional Keywords: viral protein, polyomavirus, capsid protein
• Biological source: BK polyomavirus (BKPyV, Human polyomavirus 1)
• Total number of polymer chains: 10
• Total formula weight: 304097.72

Authors

Osipov, E.M.,Beelen, S.,Strelkov, S.V. (deposition date: 2020-12-07, release date: 2022-06-22, Last modification date: 2024-01-31)

Primary citation

Osipov, E.M.,Munawar, A.H.,Beelen, S.,Fearon, D.,Douangamath, A.,Wild, C.,Weeks, S.D.,Van Aerschot, A.,von Delft, F.,Strelkov, S.V.
Discovery of novel druggable pockets on polyomavirus VP1 through crystallographic fragment-based screening to develop capsid assembly inhibitors.
Rsc Chem Biol, 3:1013-1027, 2022

PubMed Abstract: Polyomaviruses are a family of ubiquitous double-stranded DNA viruses many of which are human pathogens. These include BK polyomavirus which causes severe urinary tract infection in immunocompromised patients and Merkel cell polyomavirus associated with aggressive cancers. The small genome of polyomaviruses lacks conventional drug targets, and no specific drugs are available at present. Here we focus on the main structural protein VP1 of BK polyomavirus which is responsible for icosahedral capsid formation. To provide a foundation towards rational drug design, we crystallized truncated VP1 pentamers and subjected them to a high-throughput screening for binding drug-like fragments through a direct X-ray analysis. To enable a highly performant screening, rigorous optimization of the crystallographic pipeline and processing with the latest generation PanDDA2 software were necessary. As a result, a total of 144 binding hits were established. Importantly, the hits are well clustered in six surface pockets. Three pockets are located on the outside of the pentamer and map on the regions where the 'invading' C-terminal arm of another pentamer is attached upon capsid assembly. Another set of three pockets is situated within the wide pore along the five-fold axis of the VP1 pentamer. These pockets are situated at the interaction interface with the minor capsid protein VP2 which is indispensable for normal functioning of the virus. Here we systematically analyse the three outside pockets which are highly conserved across various polyomaviruses, while point mutations in these pockets are detrimental for viral replication. We show that one of the pockets can accommodate antipsychotic drug trifluoperazine. For each pocket, we derive pharmacophore features which enable the design of small molecules preventing the interaction between VP1 pentamers and therefore inhibiting capsid assembly. Our data lay a foundation towards a rational development of first-in-class drugs targeting polyomavirus capsid.

PubMed: 35974998
DOI: 10.1039/d2cb00052k

Experimental method

X-RAY DIFFRACTION (1.474 Å)