Structural basis for the activation of flaviviral NS3 proteases from dengue and West Nile virus.
The replication of flaviviruses requires the correct processing of their polyprotein by the viral NS3 protease (NS3pro). Essential for the activation of NS3pro is a 47-residue region of NS2B. Here we report the crystal structures of a dengue NS2B-NS3pro complex and a West Nile virus NS2B-NS3pro complex with a substrate-based inhibitor. These structures identify key residues for NS3pro substrate recognition and clarify the mechanism of NS3pro activation.
Erbel
Paul
P
Novartis Institutes for Biomedical Research, Protease Platform, 4002 Basel, Switzerland.
Schiering
Nikolaus
N
D'Arcy
Allan
A
Renatus
Martin
M
Kroemer
Markus
M
Lim
Siew Pheng
SP
Yin
Zheng
Z
Keller
Thomas H
TH
Vasudevan
Subhash G
SG
Hommel
Ulrich
U
D001665:Binding Sites; D003716:Dengue Virus / Q000201:enzymology*; D004789:Enzyme Activation; D006860:Hydrogen Bonding; D046911:Macromolecular Substances; D008958:Models, Molecular; D009842:Oligopeptides; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism; D020365:RNA Helicases / Q000737:chemistry / Q000378:metabolism; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000737:chemistry* / Q000378:metabolism*; D014902:West Nile virus / Q000201:enzymology*; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D046911:Macromolecular Substances; D009842:Oligopeptides; D011480:Protease Inhibitors; D020365:RNA Helicases; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; C080102:NS2B protein, flavivirus; C060028:NS3 protein, flavivirus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C515237:benzoyl-norleucyl-lysyl-arginyl-arginal; C504449:NS3 protease, dengue virus