7V4R

The crystal structure of KFDV NS3H bound with Pi

Summary for 7V4R

• Entry DOI: 10.2210/pdb7v4r/pdb
• Descriptor: Serine protease NS3, NICKEL (II) ION, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: kfdv, ns3 helicase, ntpase, pi, hydrolase
• Biological source: Kyasanur forest disease virus (KFDV)
• Total number of polymer chains: 1
• Total formula weight: 50522.32

Authors

Zhang, C.Y.,Jin, T.C. (deposition date: 2021-08-14, release date: 2022-08-17, Last modification date: 2023-11-29)

Primary citation

Zhang, C.,Li, Y.,Samad, A.,He, H.,Ma, H.,Chen, Y.,Jin, T.
Kyasanur Forest disease virus NS3 helicase: Insights into structure, activity, and inhibitors.
Int.J.Biol.Macromol., :127856-127856, 2023

PubMed Abstract: Kyasanur Forest disease virus (KFDV), a tick-borne flavivirus prevalent in India, presents a serious threat to human health. KFDV NS3 helicase (NS3hel) is considered a potential drug target due to its involvement in the viral replication complex. Here, we resolved the crystal structures of KFDV NS3hel apo and its complex with three phosphate molecules, which indicates a conformational switch during ATP hydrolysis. Our data revealed that KFDV NS3hel has a higher binding affinity for dsRNA, and its intrinsic ATPase activity was enhanced by dsRNA while being inhibited by DNA. Through mutagenesis analysis, several residues within motifs I, Ia, III, V, and VI were identified to be crucial for NS3hel ATPase activity. Notably, the M419A mutation drastically reduced NS3hel ATPase activity. We propose that the methionine-aromatic interaction between residues M419 and W294, located on the surface of the RNA-binding channel, could be a target for the design of efficient inhibitor probes. Moreover, epigallocatechin gallate (EGCG), a tea-derived polyphenol, strongly inhibited NS3hel ATPase activity with an IC value of 0.8 μM. Our computational docking data show that EGCG binds at the predicted druggable hotspots of NS3hel. Overall, these findings contribute to the development and design of more effective and specific inhibitors.

PubMed: 37924898
DOI: 10.1016/j.ijbiomac.2023.127856

Experimental method

X-RAY DIFFRACTION (2.1 Å)