3LKW

Crystal Structure of Dengue Virus 1 NS2B/NS3 protease active site mutant

Summary for 3LKW

• Entry DOI: 10.2210/pdb3lkw/pdb
• Related: 3L6P
• Descriptor: fusion protein of nonstructural protein 2B and nonstructural protein 3, CHLORIDE ION, CADMIUM ION, ... (6 entities in total)
• Functional Keywords: viral protease, serine protease, ns3 protease, ns2b cofactor, viral protein, hydrolase
• Biological source: Dengue virus type 1 (strain Singapore/S275/1990) (DENV-1); More
• Cellular location: Capsid protein C: Virion. Peptide pr: Secreted . Small envelope protein M: Virion membrane ; Multi-pass membrane protein . Envelope protein E: Virion membrane ; Multi-pass membrane protein . Non-structural protein 1: Secreted . Non-structural protein 2A: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Serine protease subunit NS2B: Host endoplasmic reticulum membrane; Multi-pass membrane protein . Serine protease NS3: Host endoplasmic reticulum membrane ; Peripheral membrane protein ; Cytoplasmic side . Non-structural protein 4A: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Non-structural protein 4B: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . RNA-directed RNA polymerase NS5: Host endoplasmic reticulum membrane ; Peripheral membrane protein ; Cytoplasmic side : P17763
• Total number of polymer chains: 1
• Total formula weight: 25382.90

Authors

Chandramouli, S.,Joseph, J.S.,Daudenarde, S.,Gatchalian, J.,Cornillez-Ty, C.,Kuhn, P. (deposition date: 2010-01-28, release date: 2010-03-02, Last modification date: 2024-02-21)

Primary citation

Chandramouli, S.,Joseph, J.S.,Daudenarde, S.,Gatchalian, J.,Cornillez-Ty, C.,Kuhn, P.
Serotype-specific structural differences in the protease-cofactor complexes of the dengue virus family.
J.Virol., 84:3059-3067, 2010

PubMed Abstract: With an estimated 40% of the world population at risk, dengue poses a significant threat to human health, especially in tropical and subtropical regions. Preventative and curative efforts, such as vaccine development and drug discovery, face additional challenges due to the occurrence of four antigenically distinct serotypes of the causative dengue virus (DEN1 to -4). Complex immune responses resulting from repeat assaults by the different serotypes necessitate simultaneous targeting of all forms of the virus. One of the promising targets for drug development is the highly conserved two-component viral protease NS2B-NS3, which plays an essential role in viral replication by processing the viral precursor polyprotein into functional proteins. In this paper, we report the 2.1-A crystal structure of the DEN1 NS2B hydrophilic core (residues 49 to 95) in complex with the NS3 protease domain (residues 1 to 186) carrying an internal deletion in the N terminus (residues 11 to 20). While the overall folds within the protease core are similar to those of DEN2 and DEN4 proteases, the conformation of the cofactor NS2B is dramatically different from those of other flaviviral apoprotease structures. The differences are especially apparent within its C-terminal region, implicated in substrate binding. The structure reveals for the first time serotype-specific structural elements in the dengue virus family, with the reported alternate conformation resulting from a unique metal-binding site within the DEN1 sequence. We also report the identification of a 10-residue stretch within NS3pro that separates the substrate-binding function from the catalytic turnover rate of the enzyme. Implications for broad-spectrum drug discovery are discussed.

PubMed: 20042502
DOI: 10.1128/JVI.02044-09

Experimental method

X-RAY DIFFRACTION (2 Å)