Crystal structure of the papain-like protease of MERS coronavirus reveals unusual, potentially druggable active-site features

Jian Lei; Jeroen R. Mesters; Christian Drosten; Stefan Anemüller; Qingjun Ma; Rolf Hilgenfeld

doi:10.1016/j.antiviral.2014.06.011

Crystal structure of the papain-like protease of MERS coronavirus reveals unusual, potentially druggable active-site features

Jian Lei, Jeroen R. Mesters, Christian Drosten, Stefan Anemüller, Qingjun Ma, Rolf Hilgenfeld^*

^*Corresponding author for this work

Institute of Biochemistry

74 Citations (Scopus)

Abstract

The Middle-East Respiratory Syndrome coronavirus (MERS-CoV) causes severe acute pneumonia and renal failure. The MERS-CoV papain-like protease (PL ^pro) is a potential target for the development of antiviral drugs. To facilitate these efforts, we determined the three-dimensional structure of the enzyme by X-ray crystallography. The molecule consists of a ubiquitin-like domain and a catalytic core domain. The catalytic domain displays an extended right-hand fold with a zinc ribbon and embraces a solvent-exposed substrate-binding region. The overall structure of the MERS-CoV PL^pro is similar to that of the corresponding SARS-CoV enzyme, but the architecture of the oxyanion hole and of the S3 as well as the S5 specificity sites differ from the latter. These differences are the likely reason for reduced in vitro peptide hydrolysis and deubiquitinating activities of the MERS-CoV PL ^pro, compared to the homologous enzyme from the SARS coronavirus. Introduction of a side-chain capable of oxyanion stabilization through the Leu106Trp mutation greatly enhances the in vitro catalytic activity of the MERS-CoV PL^pro. The unique features observed in the crystal structure of the MERS-CoV PL^pro should allow the design of antivirals that would not interfere with host ubiquitin-specific proteases.

Original language	English
Journal	Antiviral Research
Volume	109
Issue number	1
Pages (from-to)	72-82
Number of pages	11
ISSN	0166-3542
DOIs	https://doi.org/10.1016/j.antiviral.2014.06.011
Publication status	Published - 01.01.2014

Funding

Technical assistance by Susanne Zoske is gratefully acknowledged. We thank Linlin Zhang and Guido Hansen for discussion. We also acknowledge the staff at beamline P11 of DESY, Hamburg, Germany. This work was supported by the European Commission through its “SILVER” project (contract No. HEALTH-F3-2010-260644) and by the German Center for Infection Research (DZIF). RH acknowledges support by the DFG Cluster of Excellence “Inflammation at Interfaces” (EXC 306). This work is dedicated to Professor Wolfram Saenger on the occasion of his 75th birthday. Appendix A

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)

Coronavirus related work

Research on SARS-CoV-2 / COVID-19

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.antiviral.2014.06.011

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title = "Crystal structure of the papain-like protease of MERS coronavirus reveals unusual, potentially druggable active-site features",

abstract = "The Middle-East Respiratory Syndrome coronavirus (MERS-CoV) causes severe acute pneumonia and renal failure. The MERS-CoV papain-like protease (PL pro) is a potential target for the development of antiviral drugs. To facilitate these efforts, we determined the three-dimensional structure of the enzyme by X-ray crystallography. The molecule consists of a ubiquitin-like domain and a catalytic core domain. The catalytic domain displays an extended right-hand fold with a zinc ribbon and embraces a solvent-exposed substrate-binding region. The overall structure of the MERS-CoV PLpro is similar to that of the corresponding SARS-CoV enzyme, but the architecture of the oxyanion hole and of the S3 as well as the S5 specificity sites differ from the latter. These differences are the likely reason for reduced in vitro peptide hydrolysis and deubiquitinating activities of the MERS-CoV PL pro, compared to the homologous enzyme from the SARS coronavirus. Introduction of a side-chain capable of oxyanion stabilization through the Leu106Trp mutation greatly enhances the in vitro catalytic activity of the MERS-CoV PLpro. The unique features observed in the crystal structure of the MERS-CoV PLpro should allow the design of antivirals that would not interfere with host ubiquitin-specific proteases.",

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AU - Ma, Qingjun

AU - Hilgenfeld, Rolf

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Crystal structure of the papain-like protease of MERS coronavirus reveals unusual, potentially druggable active-site features

Abstract

Funding

Research Areas and Centers

Coronavirus related work

UN SDGs

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