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Crystal structure of the essential transcription antiterminator M2-1 protein of human respiratory syncytial virus and implications of its phosphorylation

DOI: 10.1073/pnas.1317262111 DOI Help
PMID: 24434552 PMID Help

Authors: Sian J. Tanner (University of Leeds; Public Health England) , Antonio Ariza (University of Leeds) , Charles-Adrien Richard (Unité de Virologie et Immunologie Moléculaires (UR892), Institut National de la Recherche Agronomique) , Hannah F. Kyle (University of Leeds) , Rachel L. Dods (University of Leeds) , Maire-Lise Blondot (Unité de Virologie et Immunologie Moléculaires (UR892), Institut National de la Recherche Agronomique) , Weining Wu (University of Liverpool) , Jose Trincao (Research Complex at Harwell) , Chi H. Trinh (University of Leeds) , Julian A. Hiscox (University of Liverpool) , Miles W. Carroll (Public Health England) , Nigel J. Silman (Public Health England) , Jean-Francois Eleouet (Unité de Virologie et Immunologie Moléculaires (UR892), Institut National de la Recherche Agronomique) , Thomas A. Edwards (University of Leeds) , John N. Barr (University of Leeds)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 111 (4) , PAGES 1580 - 1585

State: Published (Approved)
Published: January 2014
Diamond Proposal Number(s): 8367

Open Access Open Access

Abstract: The M2-1 protein of the important pathogen human respiratory syncytial virus is a zinc-binding transcription antiterminator that is essential for viral gene expression. We present the crystal structure of full-length M2-1 protein in its native tetrameric form at a resolution of 2.5 Å. The structure reveals that M2-1 forms a disk-like assembly with tetramerization driven by a long helix forming a four-helix bundle at its center, further stabilized by contact between the zinc-binding domain and adjacent protomers. The tetramerization helix is linked to a core domain responsible for RNA binding activity by a flexible region onwhich lie two functionally critical serine residues that are phosphorylated during infection. The crystal structure of a phosphomimetic M2-1 variant revealed altered charge density surrounding this flexible region although its position was unaffected. Structure-guided mutagenesis identified residues that contributed to RNA binding and antitermination activity, revealing a strong correlation between these two activities, and further defining the role of phosphorylation in M2-1 antitermination activity. The data we present here identify surfaces critical for M2-1 function that may be targeted by antiviral compounds.

Journal Keywords: Crystallography; X-Ray; Humans; Nuclear; Biomolecular; Phosphorylation; Protein; RNA; Respiratory; Viral Proteins

Diamond Keywords: Human Respiratory Syncytial Virus (HRSV) ; Viruses

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I02-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 24/03/2014 11:57


Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX) Single Wavelength Anomalous Diffraction (SAD)