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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
PMID:
24434552
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

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
Documents:
pnas.1317262111.pdf
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)