Structural Basis for the Acylation Reaction of Alphacoronavirus 3C-like Protease

Junwei Zhou; Jiyao Chen; Peng Sun; Gang Ye; Yuanqing Wang; Runhui Qiu; Zhixiang Yang; Dengguo Wei; Guiqing Peng; Liurong Fang; Shaobo Xiao

doi:10.1021/acscatal.4c01159

Structural Basis for the Acylation Reaction of Alphacoronavirus 3C-like Protease

Junwei Zhou, Jiyao Chen, Peng Sun, Gang Ye, Yuanqing Wang, Runhui Qiu, Zhixiang Yang, Dengguo Wei, Guiqing Peng, Liurong Fang, Shaobo Xiao

Research output: Contribution to journal › Article › peer-review

Abstract

Coronavirus 3C-like proteases (3CL^pro) are critical for viral replication and provide targets for antiviral drugs. Using the enteropathogenic alphacoronavirus porcine epidemic diarrhea virus (PEDV) as a model, we determined the crystal structure of an inactive PEDV 3CL^pro variant (C144A) in complex with a peptide of NF-κB essential modulator (NEMO_227-233). Structural characterization showed that the conformational change to PEDV 3CL^pro S1′ pocket conferred tolerance for nonconventional P1′-Val from a NEMO peptide substrate, indicating strong substrate accommodation. Using a combination of classical and quantum mechanics/molecular mechanics simulations, we explored the free-energy landscapes associated with the acylation step of PEDV 3CL^pro with regard to various substrates. The P1′ site plays a key role in the thermodynamics and kinetics of proteolysis, and the S1′ pocket might affect the free-energy cost of the acylation reaction. Our study provides structural insight into coronavirus 3CL^pro-mediated cleavage and will inform the development of anti-coronavirus drugs.

Original language	English (US)
Pages (from-to)	8330-8342
Number of pages	13
Journal	ACS Catalysis
Volume	14
Issue number	11
DOIs	https://doi.org/10.1021/acscatal.4c01159
State	Published - Jun 7 2024
Externally published	Yes

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Publisher Copyright:
© 2024 American Chemical Society.

Keywords

3CL protease
QM/MM
acylation
crystal structure
minimum free-energy path
molecular dynamics
porcine epidemic diarrhea virus

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10.1021/acscatal.4c01159

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title = "Structural Basis for the Acylation Reaction of Alphacoronavirus 3C-like Protease",

abstract = "Coronavirus 3C-like proteases (3CLpro) are critical for viral replication and provide targets for antiviral drugs. Using the enteropathogenic alphacoronavirus porcine epidemic diarrhea virus (PEDV) as a model, we determined the crystal structure of an inactive PEDV 3CLpro variant (C144A) in complex with a peptide of NF-κB essential modulator (NEMO227-233). Structural characterization showed that the conformational change to PEDV 3CLpro S1′ pocket conferred tolerance for nonconventional P1′-Val from a NEMO peptide substrate, indicating strong substrate accommodation. Using a combination of classical and quantum mechanics/molecular mechanics simulations, we explored the free-energy landscapes associated with the acylation step of PEDV 3CLpro with regard to various substrates. The P1′ site plays a key role in the thermodynamics and kinetics of proteolysis, and the S1′ pocket might affect the free-energy cost of the acylation reaction. Our study provides structural insight into coronavirus 3CLpro-mediated cleavage and will inform the development of anti-coronavirus drugs.",

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author = "Junwei Zhou and Jiyao Chen and Peng Sun and Gang Ye and Yuanqing Wang and Runhui Qiu and Zhixiang Yang and Dengguo Wei and Guiqing Peng and Liurong Fang and Shaobo Xiao",

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AU - Zhou, Junwei

AU - Chen, Jiyao

AU - Sun, Peng

AU - Ye, Gang

AU - Wang, Yuanqing

AU - Qiu, Runhui

AU - Yang, Zhixiang

AU - Wei, Dengguo

AU - Peng, Guiqing

AU - Fang, Liurong

AU - Xiao, Shaobo

PY - 2024/6/7

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N2 - Coronavirus 3C-like proteases (3CLpro) are critical for viral replication and provide targets for antiviral drugs. Using the enteropathogenic alphacoronavirus porcine epidemic diarrhea virus (PEDV) as a model, we determined the crystal structure of an inactive PEDV 3CLpro variant (C144A) in complex with a peptide of NF-κB essential modulator (NEMO227-233). Structural characterization showed that the conformational change to PEDV 3CLpro S1′ pocket conferred tolerance for nonconventional P1′-Val from a NEMO peptide substrate, indicating strong substrate accommodation. Using a combination of classical and quantum mechanics/molecular mechanics simulations, we explored the free-energy landscapes associated with the acylation step of PEDV 3CLpro with regard to various substrates. The P1′ site plays a key role in the thermodynamics and kinetics of proteolysis, and the S1′ pocket might affect the free-energy cost of the acylation reaction. Our study provides structural insight into coronavirus 3CLpro-mediated cleavage and will inform the development of anti-coronavirus drugs.

AB - Coronavirus 3C-like proteases (3CLpro) are critical for viral replication and provide targets for antiviral drugs. Using the enteropathogenic alphacoronavirus porcine epidemic diarrhea virus (PEDV) as a model, we determined the crystal structure of an inactive PEDV 3CLpro variant (C144A) in complex with a peptide of NF-κB essential modulator (NEMO227-233). Structural characterization showed that the conformational change to PEDV 3CLpro S1′ pocket conferred tolerance for nonconventional P1′-Val from a NEMO peptide substrate, indicating strong substrate accommodation. Using a combination of classical and quantum mechanics/molecular mechanics simulations, we explored the free-energy landscapes associated with the acylation step of PEDV 3CLpro with regard to various substrates. The P1′ site plays a key role in the thermodynamics and kinetics of proteolysis, and the S1′ pocket might affect the free-energy cost of the acylation reaction. Our study provides structural insight into coronavirus 3CLpro-mediated cleavage and will inform the development of anti-coronavirus drugs.

KW - 3CL protease

KW - QM/MM

KW - acylation

KW - crystal structure

KW - minimum free-energy path

KW - molecular dynamics

KW - porcine epidemic diarrhea virus

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Structural Basis for the Acylation Reaction of Alphacoronavirus 3C-like Protease

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