Issue 21, 2021

Mechanism of zinc ejection by disulfiram in nonstructural protein 5A

Abstract

Hepatitis C virus (HCV) is a notorious member of the Flaviviridae family of enveloped, positive-strand RNA viruses. Non-structural protein 5A (NS5A) plays a key role in HCV replication and assembly. NS5A is a multi-domain protein which includes an N-terminal amphipathic membrane anchoring alpha helix, a highly structured domain-1, and two intrinsically disordered domains 2–3. The highly structured domain-1 contains a zinc finger (Zf)-site, and binding of zinc stabilizes the overall structure, while ejection of this zinc from the Zf-site destabilizes the overall structure. Therefore, NS5A is an attractive target for anti-HCV therapy by disulfiram, through ejection of zinc from the Zf-site. However, the zinc ejection mechanism is poorly understood. To disclose this mechanism based on three different states, A-state (NS5A protein), B-state (NS5A + Zn), and C-state (NS5A + Zn + disulfiram), we have performed molecular dynamics (MD) simulation in tandem with DFT calculations in the current study. The MD results indicate that disulfiram triggers Zn ejection from the Zf-site predominantly through altering the overall conformation ensemble. On the other hand, the DFT assessment demonstrates that the Zn adopts a tetrahedral configuration at the Zf-site with four Cys residues, which indicates a stable protein structure morphology. Disulfiram binding induces major conformational changes at the Zf-site, introduces new interactions of Cys39 with disulfiram, and further weakens the interaction of this residue with Zn, causing ejection of zinc from the Zf-site. The proposed mechanism elucidates the therapeutic potential of disulfiram and offers theoretical guidance for the advancement of drug candidates.

Graphical abstract: Mechanism of zinc ejection by disulfiram in nonstructural protein 5A

Article information

Article type
Paper
Submitted
08 Dec 2020
Accepted
27 Apr 2021
First published
29 Apr 2021

Phys. Chem. Chem. Phys., 2021,23, 12204-12215

Mechanism of zinc ejection by disulfiram in nonstructural protein 5A

A. U. Rehman, G. Zhen, B. Zhong, D. Ni, J. Li, A. Nasir, M. T. Gabr, H. Rafiq, A. Wadood, S. Lu, J. Zhang and H. Chen, Phys. Chem. Chem. Phys., 2021, 23, 12204 DOI: 10.1039/D0CP06360F

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