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A sialic acid binding site in a human picornavirus

DOI: 10.1371/journal.ppat.1004401 DOI Help
PMID: 25329320 PMID Help

Authors: Georg Zocher (University Tübingen) , Nitesh Mistry (Umeå University) , Martin Frank (Biognos AB) , Irmgard Haehnlein-Schick (University Tübingen) , Jens-Ola Ekström (Umeå University) , Niklas Arnberg (Umeå University) , Thilo Stehle (University Tübingen; Vanderbilt University School of Medicine)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Plos Pathogens , VOL 10 (10)

State: Published (Approved)
Published: October 2014

Open Access Open Access

Abstract: The picornaviruses coxsackievirus A24 variant (CVA24v) and enterovirus 70 (EV70) cause continued outbreaks and pandemics of acute hemorrhagic conjunctivitis (AHC), a highly contagious eye disease against which neither vaccines nor antiviral drugs are currently available. Moreover, these viruses can cause symptoms in the cornea, upper respiratory tract, and neurological impairments such as acute flaccid paralysis. EV70 and CVA24v are both known to use 5-N-acetylneuraminic acid (Neu5Ac) for cell attachment, thus providing a putative link between the glycan receptor specificity and cell tropism and disease. We report the structures of an intact human picornavirus in complex with a range of glycans terminating in Neu5Ac. We determined the structure of the CVA24v to 1.40 Å resolution, screened different glycans bearing Neu5Ac for CVA24v binding, and structurally characterized interactions with candidate glycan receptors. Biochemical studies verified the relevance of the binding site and demonstrated a preference of CVA24v for α2,6-linked glycans. This preference can be rationalized by molecular dynamics simulations that show that α2,6-linked glycans can establish more contacts with the viral capsid. Our results form an excellent platform for the design of antiviral compounds to prevent AHC.

Journal Keywords: Viral packaging; Sialic acids; Virions; Picornaviruses; Viral structure; Crystal structure; Electron density; Coxsackieviruses

Diamond Keywords: Viruses

Subject Areas: Biology and Bio-materials, Medicine, Chemistry


Instruments: I03-Macromolecular Crystallography

Added On: 24/02/2015 09:16

Documents:
journal.ppat.1004401.pdf

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Biochemistry Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)