pH-dependent conformational flexibility of the SARS-CoV main proteinase (Mpro) dimer: Molecular dynamics simulations and multiple X-ray structure analyses

Jinzhi Tan; Koen H.G. Verschueren; Kanchan Anand; Jianhua Shen; Maojun Yang; Yechun Xu; Zihe Rao; Janna Bigalke; Burkhard Heisen; Jeroen R. Mesters; Kaixian Chen; Xu Shen; Hualiang Jiang; Rolf Hilgenfeld

doi:10.1016/j.jmb.2005.09.012

pH-dependent conformational flexibility of the SARS-CoV main proteinase (M^pro) dimer: Molecular dynamics simulations and multiple X-ray structure analyses

Jinzhi Tan, Koen H.G. Verschueren, Kanchan Anand, Jianhua Shen, Maojun Yang, Yechun Xu, Zihe Rao, Janna Bigalke, Burkhard Heisen, Jeroen R. Mesters, Kaixian Chen, Xu Shen, Hualiang Jiang^*, Rolf Hilgenfeld

^*Corresponding author for this work

Institute of Biochemistry

165 Citations (Scopus)

Abstract

The SARS coronavirus main proteinase (M^pro) is a key enzyme in the processing of the viral polyproteins and thus an attractive target for the discovery of drugs directed against SARS. The enzyme has been shown by X-ray crystallography to undergo significant pH-dependent conformational changes. Here, we assess the conformational flexibility of the M^pro by analysis of multiple crystal structures (including two new crystal forms) and by molecular dynamics (MD) calculations. The MD simulations take into account the different protonation states of two histidine residues in the substrate-binding site and explain the pH-activity profile of the enzyme. The low enzymatic activity of the M^pro monomer and the need for dimerization are also discussed.

Original language	English
Journal	Journal of Molecular Biology
Volume	354
Issue number	1
Pages (from-to)	25-40
Number of pages	16
ISSN	0022-2836
DOIs	https://doi.org/10.1016/j.jmb.2005.09.012
Publication status	Published - 18.11.2005

Funding

We are grateful to Walter Verheyen for expert technical assistance. This work was supported by the Sino-European Project on SARS Diagnostics and Antivirals (SEPSDA) of the European Commission (contract no. SP22-CT-2004-003831), the Sino-German Center for the Promotion of Science (Beijing, grant no. GZ 233 - 202/6), the Deutsche Forschungsgemeinschaft (Hi 611/4-1), the Shanghai Basic Research Project from the Shanghai Science and Technology Commission (grant 02DJ14070, 03DZ19212), the National Natural Science Foundation of China (grants 20372069, 29725203 and 20072042), the State Key Program of Basic Research of China (grants 2003CB514125, 2003CB514124, 2002CB512807 and 2002CB512802), the 863 Hi-Tech Program (grants 2001AA235051, 2001AA235071 and 2002AA3301), and the special programs on fighting SARS of the Ministry of Science and Technology, Chinese Academy of Sciences, National Natural Science Foundation of China and Shanghai Science and Technology Commission. M.Y. was supported by a stipend from the University of Lübeck. R.H. thanks the Fonds der Chemischen Industrie for continuous support.

UN SDGs

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

SDG 3 Good Health and Well-being

Research Areas and Centers

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

Coronavirus related work

Research on SARS-CoV-2 / COVID-19

Access to Document

10.1016/j.jmb.2005.09.012

Cite this

Tan, J., Verschueren, K. H. G., Anand, K., Shen, J., Yang, M., Xu, Y., Rao, Z., Bigalke, J., Heisen, B., Mesters, J. R., Chen, K., Shen, X., Jiang, H., & Hilgenfeld, R. (2005). pH-dependent conformational flexibility of the SARS-CoV main proteinase (M^pro) dimer: Molecular dynamics simulations and multiple X-ray structure analyses. Journal of Molecular Biology, 354(1), 25-40. https://doi.org/10.1016/j.jmb.2005.09.012

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title = "pH-dependent conformational flexibility of the SARS-CoV main proteinase (Mpro) dimer: Molecular dynamics simulations and multiple X-ray structure analyses",

abstract = "The SARS coronavirus main proteinase (Mpro) is a key enzyme in the processing of the viral polyproteins and thus an attractive target for the discovery of drugs directed against SARS. The enzyme has been shown by X-ray crystallography to undergo significant pH-dependent conformational changes. Here, we assess the conformational flexibility of the Mpro by analysis of multiple crystal structures (including two new crystal forms) and by molecular dynamics (MD) calculations. The MD simulations take into account the different protonation states of two histidine residues in the substrate-binding site and explain the pH-activity profile of the enzyme. The low enzymatic activity of the Mpro monomer and the need for dimerization are also discussed.",

author = "Jinzhi Tan and Verschueren, \{Koen H.G.\} and Kanchan Anand and Jianhua Shen and Maojun Yang and Yechun Xu and Zihe Rao and Janna Bigalke and Burkhard Heisen and Mesters, \{Jeroen R.\} and Kaixian Chen and Xu Shen and Hualiang Jiang and Rolf Hilgenfeld",

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Tan, J, Verschueren, KHG, Anand, K, Shen, J, Yang, M, Xu, Y, Rao, Z, Bigalke, J, Heisen, B, Mesters, JR, Chen, K, Shen, X, Jiang, H & Hilgenfeld, R 2005, 'pH-dependent conformational flexibility of the SARS-CoV main proteinase (M^pro) dimer: Molecular dynamics simulations and multiple X-ray structure analyses', Journal of Molecular Biology, vol. 354, no. 1, pp. 25-40. https://doi.org/10.1016/j.jmb.2005.09.012

pH-dependent conformational flexibility of the SARS-CoV main proteinase (M^pro) dimer: Molecular dynamics simulations and multiple X-ray structure analyses. / Tan, Jinzhi; Verschueren, Koen H.G.; Anand, Kanchan et al.
In: Journal of Molecular Biology, Vol. 354, No. 1, 18.11.2005, p. 25-40.

Research output: Journal Articles › Journal articles › Research › peer-review

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AU - Verschueren, Koen H.G.

AU - Anand, Kanchan

AU - Shen, Jianhua

AU - Yang, Maojun

AU - Xu, Yechun

AU - Rao, Zihe

AU - Bigalke, Janna

AU - Heisen, Burkhard

AU - Mesters, Jeroen R.

AU - Chen, Kaixian

AU - Shen, Xu

AU - Jiang, Hualiang

AU - Hilgenfeld, Rolf

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