4UCA

N-terminal globular domain of the RSV Nucleoprotein in complex with C- terminal peptide of the Phosphoprotein

Summary for 4UCA

• Entry DOI: 10.2210/pdb4uca/pdb
• Related: 4UC6 4UC7 4UC8 4UC9 4UCB 4UCC 4UCD 4UCE
• Descriptor: NUCLEOPROTEIN, PHOSPHOSPROTEIN, SULFATE ION, ... (4 entities in total)
• Functional Keywords: viral protein, ribonucleoprotein, nucleocapsid, phosphoprotein, antiviral compounds, halogen bond
• Biological source: HUMAN RESPIRATORY SYNCYTIAL VIRUS A2; More
• Cellular location: Virion: P03418
• Total number of polymer chains: 3
• Total formula weight: 53230.21

Authors

Ouizougun-Oubari, M.,Pereira, N.,Tarus, B.,Galloux, M.,Tortorici, M.-A.,Hoos, S.,Baron, B.,England, P.,Bontems, F.,Rey, F.A.,Eleouet, J.-F.,Sizun, C.,Slama-Schwok, A.,Duquerroy, S. (deposition date: 2014-12-03, release date: 2015-08-19, Last modification date: 2023-12-20)

Primary citation

Ouizougun-Oubari, M.,Pereira, N.,Tarus, B.,Galloux, M.,Lassoued, S.,Fix, J.,Tortorici, M.A.,Hoos, S.,Baron, B.,England, P.,Desmaele, D.,Couvreur, P.,Bontems, F.,Rey, F.A.,Eleouet, J.F.,Sizun, C.,Slama-Schwok, A.,Duquerroy, S.
A Druggable Pocket at the Nucleocapsid/Phosphoprotein Interaction Site of the Human Respiratory Syncytial Virus.
J.Virol., 89:11129-, 2015

PubMed Abstract: Presently, respiratory syncytial virus (RSV), the main cause of severe respiratory infections in infants, cannot be treated efficiently with antivirals. However, its RNA-dependent polymerase complex offers potential targets for RSV-specific drugs. This includes the recognition of its template, the ribonucleoprotein complex (RNP), consisting of genomic RNA encapsidated by the RSV nucleoprotein, N. This recognition proceeds via interaction between the phosphoprotein P, which is the main polymerase cofactor, and N. The determinant role of the C terminus of P, and more particularly of the last residue, F241, in RNP binding and viral RNA synthesis has been assessed previously. Here, we provide detailed structural insight into this crucial interaction for RSV polymerase activity. We solved the crystallographic structures of complexes between the N-terminal domain of N (N-NTD) and C-terminal peptides of P and characterized binding by biophysical approaches. Our results provide a rationale for the pivotal role of F241, which inserts into a well-defined N-NTD pocket. This primary binding site is completed by transient contacts with upstream P residues outside the pocket. Based on the structural information of the N-NTD:P complex, we identified inhibitors of this interaction, selected by in silico screening of small compounds, that efficiently bind to N and compete with P in vitro. One of the compounds displayed inhibitory activity on RSV replication, thereby strengthening the relevance of N-NTD for structure-based design of RSV-specific antivirals.

PubMed: 26246564
DOI: 10.1128/JVI.01612-15

Experimental method

X-RAY DIFFRACTION (3.22 Å)