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Title: Crystal structures of alphavirus nonstructural protein 4 (nsP4) reveal an intrinsically dynamic RNA-dependent RNA polymerase fold
Authors: Tan, Yaw Bia
Lello, Laura Sandra
Liu, Xin
Law, Yee-Song
Kang, Congbao
Lescar, Julien
Zheng, Jie
Merits, Andres
Luo, Dahai
Keywords: Science::Medicine
Science::Biological sciences
Issue Date: 2022
Source: Tan, Y. B., Lello, L. S., Liu, X., Law, Y., Kang, C., Lescar, J., Zheng, J., Merits, A. & Luo, D. (2022). Crystal structures of alphavirus nonstructural protein 4 (nsP4) reveal an intrinsically dynamic RNA-dependent RNA polymerase fold. Nucleic Acids Research, 50(2), 1000-1016.
Project: MOET2EP30220-0009
Journal: Nucleic Acids Research
Abstract: Alphaviruses such as Ross River virus (RRV), chikungunya virus (CHIKV), Sindbis virus (SINV), and Venezuelan equine encephalitis virus (VEEV) are mosquito-borne pathogens that can cause arthritis or encephalitis diseases. Nonstructural protein 4 (nsP4) of alphaviruses possesses RNA-dependent RNA polymerase (RdRp) activity essential for viral RNA replication. No 3D structure has been available for nsP4 of any alphaviruses despite its importance for understanding alphaviral RNA replication and for the design of antiviral drugs. Here, we report crystal structures of the RdRp domain of nsP4 from both RRV and SINV determined at resolutions of 2.6 Å and 1.9 Å. The structure of the alphavirus RdRp domain appears most closely related to RdRps from pestiviruses, noroviruses, and picornaviruses. Hydrogen-deuterium exchange mass spectrometry (HDX-MS) and nuclear magnetic resonance (NMR) methods showed that in solution, nsP4 is highly dynamic with an intrinsically disordered N-terminal domain. Both full-length nsP4 and the RdRp domain were capable to catalyze RNA polymerization. Structure-guided mutagenesis using a trans-replicase system identified nsP4 regions critical for viral RNA replication.
ISSN: 0305-1048
DOI: 10.1093/nar/gkab1302
Schools: Lee Kong Chian School of Medicine (LKCMedicine) 
School of Biological Sciences 
Research Centres: NTU Institute of Structural Biology 
Rights: © The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (, which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles
SBS Journal Articles

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