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Cross-linking mass spectrometry and integrative structural modelling identifies compact conformation of DENV NS2B to NS3

ABSTRACT: Dengue virus remains a public health threat. Dengue NS2B-NS3 proteins are prime antiviral drug targets and have been studied extensively. Here, we combine cross-linking mass spectrometry, molecular dynamics simulations and biochemical assays to identify NS2B-NS3 full length interactions. Using cross-linkers of different lengths as molecular rulers, we identified NS2B S48 as a key interacting residue that has not been previously reported. Molecular dynamics simulations modelled a compact conformation of NS2B to NS3 interaction with better agreement to cross-link data. In contrast, previously reported crystal structure indicated an elongated conformation with poor agreement to cross-link data. Mutation of NS2B S48 to alanine or lysine greatly reduces protease activity and disrupts the NS2B S48 binding pocket in the compact conformation. NS2B-NS3 cross-links were also found to be conserved across all four dengue serotypes. Our interdisciplinary approach reveals new key interacting residue and a compact conformation that can guide drug development against dengue.

ORGANISM(S): Cellular Organisms

SUBMITTER: Radoslaw Sobota

PROVIDER: PXD063379 | JPOST Repository | Fri Dec 19 00:00:00 GMT 2025

REPOSITORIES: jPOST

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			Action	DRS
	20231005_Lumos_ZS_WP_eD4FL_100x_R1.raw	Raw
	20231005_Lumos_ZS_WP_eD4FL_100x_R2.raw	Raw
	20231215_Lumos_ZS_WP_eD4FL_S48A_dsso_T1.raw	Raw
	20231215_Lumos_ZS_WP_eD4FL_S48A_dsso_T2.raw	Raw
	20231215_Lumos_ZS_WP_eD4FL_S48A_dsso_T3.raw	Raw

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Cross-linking mass spectrometry and integrative structural modelling identifies compact conformation of DENV NS2B to NS3

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