Structural basis for the activation of flaviviral NS3 proteases from dengue and West Nile virus

Erbel, P.; Schiering, Nikolaus; D’Arcy, Allan; Renatus, Martin; Kroemer, M.; Lim, Siew Pheng; Yin, Zheng; Keller, Thomas H.; Vasudevan, Subhash G.; Hommel, Ulrich

doi:10.1038/nsmb1073

Cited by 515 publications

(924 citation statements)

References 13 publications

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“…65 Several tetrapeptides containing a C-terminal arginal or other aldehydes were reported by Knox with IC 50 values range between 1 and 200 µM. 46 The most potent inhibitors and their IC 50 of this series are shown in Table 1.3. Later, additional arginal derivatives have been reported by Stoermer et al.…”

Section: Known Wnv Ns2b-ns3 Protease Inhibitorsmentioning

confidence: 91%

“…46 The main role of NS3 protease is the catalytic processing of the polyprotein to generate the single mature nonstructural proteins (Figure 1.6). 41 To exhibit the artificial heterocomplex, the NS2B-NS3, is depicted in the enlarged section (figure was adopted from Lescar et al).…”

Section: The Biological Roles Of the Nonstructural Viral Proteinsmentioning

confidence: 99%

“…51,52 A crystal structure of the recombinant NS2B40-G4SG4-NS3 protein domain has been resolved illustrating that NS2B40 wraps around NS3 protein in a belt-like manner. 46,53 This suggests that NS2B may function as a cofactor to NS3, facilitating the arrangement of the catalytic triad into an active conformation. 27 The other nonstructural viral proteins NS2A, NS4A, and NS4B are small, hydrophobic proteins and may facilitate the assembly of viral replication complexes and/or their localization on cytoplasmic membranes.…”

Section: The Biological Roles Of the Nonstructural Viral Proteinsmentioning

confidence: 99%

“…. 46 An additional structure was solved in complex with the aldehyde 2-naphthoyl-Lys-LysArg-H (3e90.pdb). 77 The structure revealed that the carbonyl oxygen of the P1 aldehyde is attacked by the serine hydroxyl and forms a tetrahedral hemiacetal.…”

Section: Crystal Structures Of the Wnv Proteasementioning

confidence: 99%

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Development and Characterization of New Peptidomimetic Inhibitors of the West Nile Virus NS2B–NS3 Protease

et al. 2013

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A series of new substrate analogue inhibitors of the WNV NS2B–NS3 protease containing decarboxylated arginine mimetics at the P1 position was developed. Among the various analogues, trans‐(4‐guanidino)cyclohexylmethylamide (GCMA) was identified as the most suitable P1 residue. In combination with dichloro‐substituted phenylacetyl groups at the P4 position, three inhibitors with inhibition constants of <0.2 μM were obtained. These GCMA inhibitors have a better selectivity profile than the previously described agmatine analogues, and possess negligible affinity for the trypsin‐like serine proteases thrombin, factor Xa, and matriptase. A crystal structure in complex with the WNV protease was determined for one of the most potent inhibitors, 3,4‐dichlorophenylacetyl‐Lys‐Lys‐GCMA (Ki=0.13 μM). The inhibitor adopts a horseshoe‐like conformation, most likely due to a hydrophobic contact between the P4 phenyl ring and the P1 cyclohexyl group, which is further stabilized by an intramolecular hydrogen bond between the P1 guanidino group and the P4 carbonyl oxygen atom. These inhibitors are stable, readily accessible, and have a noncovalent binding mode. Therefore, they may serve as suitable lead structures for further development.

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Section: Known Wnv Ns2b-ns3 Protease Inhibitorsmentioning

confidence: 91%

Section: The Biological Roles Of the Nonstructural Viral Proteinsmentioning

confidence: 99%

Section: The Biological Roles Of the Nonstructural Viral Proteinsmentioning

confidence: 99%

Section: Crystal Structures Of the Wnv Proteasementioning

confidence: 99%

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Development and Characterization of New Peptidomimetic Inhibitors of the West Nile Virus NS2B–NS3 Protease

et al. 2013

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“…The catalytic triad (His51-Asp75-Ser135) is located at the cleft between the two β-barrels, and the two β-barrels are surrounded by NS2B. In the absence of an inhibitor or substrate, the apo ZIKV NS2B-NS3pro adopts a "relaxed conformation" similar to other flavivirus NS2B-NS3pros [14]. The root-mean-square deviations between ZIKV NS2B-NS3pro and those of WNV and DENV proteases are ~1.3 Å (for Cα; PDB IDs: 2YOL and 3L6P).…”

mentioning

confidence: 99%

Mechanisms of activation and inhibition of Zika virus NS2B-NS3 protease

Chen

Yang

et al. 2016

Cell Res

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Structural characterization of the linked NS2B‐NS3 protease of Zika virus

Phoo

Loh

et al. 2017

FEBS Letters

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The Zika virus (ZIKV) NS2B-NS3 protease is an important drug target. The conventional flaviviral protease constructs used for structural studies contain the NS2B cofactor region linked to the NS3 protease domain via a glycine-rich flexible linker. Here, we examined the structural dynamics of this conventional Zika protease (gZiPro) using NMR spectroscopy. Although the glycine-rich linker in gZiPro does not alter the overall folding of the protease in solution, gZiPro is not homogenous in ion exchange chromatography. Compared to the unlinked protease construct, the artificial linker affects the chemical environment of many residues including H51 in the catalytic triad. Our study provides a direct comparison of ZIKV protease constructs with and without an artificial linker.

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Structural basis for the activation of flaviviral NS3 proteases from dengue and West Nile virus

Cited by 515 publications

References 13 publications

Development and Characterization of New Peptidomimetic Inhibitors of the West Nile Virus NS2B–NS3 Protease

Development and Characterization of New Peptidomimetic Inhibitors of the West Nile Virus NS2B–NS3 Protease

Mechanisms of activation and inhibition of Zika virus NS2B-NS3 protease

Structural characterization of the linked NS2B‐NS3 protease of Zika virus

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