8F2Q

Human Parvovirus B19 Nonstructural NS1 Protein NLS bound to Importin Alpha 2

Summary for 8F2Q

• Entry DOI: 10.2210/pdb8f2q/pdb
• Descriptor: Importin subunit alpha-1, Initiator protein NS1 (2 entities in total)
• Functional Keywords: importin, nuclear, transport, nls, transport protein
• Biological source: Mus musculus (house mouse); More
• Total number of polymer chains: 3
• Total formula weight: 57639.36

Authors

Cross, E.M.,Forwood, J.K. (deposition date: 2022-11-08, release date: 2023-05-03, Last modification date: 2023-10-25)

Primary citation

Alvisi, G.,Manaresi, E.,Cross, E.M.,Hoad, M.,Akbari, N.,Pavan, S.,Ariawan, D.,Bua, G.,Petersen, G.F.,Forwood, J.,Gallinella, G.
Importin alpha / beta-dependent nuclear transport of human parvovirus B19 nonstructural protein 1 is essential for viral replication.
Antiviral Res., 213:105588-105588, 2023

PubMed Abstract: Human parvovirus B19 (B19V) is a major human pathogen causing a variety of diseases, characterized by a selective tropism to human progenitor cells in bone marrow. In similar fashion to all Parvoviridae members, the B19V ssDNA genome is replicated within the nucleus of infected cells through a process which involves both cellular and viral proteins. Among the latter, a crucial role is played by non-structural protein (NS)1, a multifunctional protein involved in genome replication and transcription, as well as modulation of host gene expression and function. Despite the localization of NS1 within the host cell nucleus during infection, little is known regarding the mechanism of its nuclear transport pathway. In this study we undertake structural, biophysical, and cellular approaches to characterize this process. Quantitative confocal laser scanning microscopy (CLSM), gel mobility shift, fluorescence polarization and crystallographic analysis identified a short sequence of amino acids (GACHAKKPRIT-182) as the classical nuclear localization signal (cNLS) responsible for nuclear import, mediated in an energy and importin (IMP) α/β-dependent fashion. Structure-guided mutagenesis of key residue K177 strongly impaired IMPα binding, nuclear import, and viral gene expression in a minigenome system. Further, treatment with ivermectin, an antiparasitic drug interfering with the IMPα/β dependent nuclear import pathway, inhibited NS1 nuclear accumulation and viral replication in infected UT7/Epo-S1 cells. Thus, NS1 nuclear transport is a potential target of therapeutic intervention against B19V induced disease.

PubMed: 36990397
DOI: 10.1016/j.antiviral.2023.105588

Experimental method

X-RAY DIFFRACTION (2.7 Å)