Glutathione facilitates enterovirus assembly by binding at a druggable pocket

DOI: 10.1038/s42003-019-0722-x

Authors: Helen M. E. Duyvesteyn (University of Oxford; Diamond Light Source) , Jingshan Ren (University of Oxford) , Thomas S. Walter (University of Oxford) , Elizabeth E. Fry (University of Oxford) , David I. Stuart (University of Oxford; Diamond Light Source)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Communications Biology , VOL 3

State: Published (Approved)
Published: January 2020
Diamond Proposal Number(s): 19946

Abstract: Enteroviruses cause a range of human and animal diseases, some life-threatening, but there remain no licenced anti-enterovirus drugs. However, a benzene-sulfonamide derivative and related compounds have been shown recently to block infection of a range of enteroviruses by binding the capsid at a positively-charged surface depression conserved across many enteroviruses. It has also been established that glutathione is essential for the assembly of many enteroviruses, interacting with the capsid proteins to facilitate the formation of the pentameric assembly intermediate, although the mechanism is unknown. Here we show, by high resolution structure analyses of enterovirus F3, that reduced glutathione binds to the same interprotomer pocket as the benzene-sulfonamide derivative. Bound glutathione makes strong interactions with adjacent protomers, thereby explaining the underlying biological role of this druggable binding pocket and delineating the pharmacophore for potential antivirals.

Journal Keywords: Antivirals; Molecular medicine; Virus structures; X-ray crystallography

Diamond Keywords: Viruses

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography

Added On: 09/01/2020 14:59

Documents:
s42003-019-0722-x.pdf

Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX)