Evidence map›Paper›PMID 24164286›Full record

ArticleACS chemical biology2013

Allosteric inhibition of the NS2B-NS3 protease from dengue virus.

Muslum Yildiz, Sumana Ghosh, Jeffrey A Bell, Woody Sherman, Jeanne A Hardy

Open access · greenAbstract read
In one paragraph

Article in ACS chemical biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.

0numbers the graph read from it
0cells of the map it votes in
60citing papers in PubMed
8.5field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

60 citing papers in PubMed, 149 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

5 authors at 2 institutions in 1 country.

Muslum YildizDepartment of Chemistry, University of Massachusetts , 104 LGRT, 710 N. Pleasant St., Amherst, Massachussetts 01003, United States.
Sumana Ghosh
Jeffrey A Bell
Woody Sherman
Jeanne A Hardy
University of Massachusetts Amherst · USSchrodinger (United States) · US

Funding

NIGMS NIH HHS Y01 GM000080
6 · The paper itself

Abstract

Dengue virus is the flavivirus that causes dengue fever, dengue hemorrhagic disease, and dengue shock syndrome, which are currently increasing in incidence worldwide. Dengue virus protease (NS2B-NS3pro) is essential for dengue virus infection and is thus a target of therapeutic interest. To date, attention has focused on developing active-site inhibitors of NS2B-NS3pro. The flat and charged nature of the NS2B-NS3pro active site may contribute to difficulties in developing inhibitors and suggests that a strategy of identifying allosteric sites may be useful. We report an approach that allowed us to scan the NS2B-NS3pro surface by cysteine mutagenesis and use cysteine reactive probes to identify regions of the protein that are susceptible to allosteric inhibition. This method identified a new allosteric site utilizing a circumscribed panel of just eight cysteine variants and only five cysteine reactive probes. The allosterically sensitive site is centered at Ala125, between the 120s loop and the 150s loop. The crystal structures of WT and modified NS2B-NS3pro demonstrate that the 120s loop is flexible. Our work suggests that binding at this site prevents a conformational rearrangement of the NS2B region of the protein, which is required for activation. Preventing this movement locks the protein into the open, inactive conformation, suggesting that this site may be useful in the future development of therapeutic allosteric inhibitors.

Indexed as

Allosteric RegulationAllosteric SiteAntiviral AgentsCatalytic DomainCysteineDengue VirusEnzyme ActivationKineticsMolecular Docking SimulationMolecular ProbesMutationProtease InhibitorsProtein BindingProtein Structure, SecondaryProtein Structure, TertiarySerine EndopeptidasesAntiviral AgentsCysteineMolecular ProbesNS2B protein, flavivirusNS3 protease, dengue virusProtease InhibitorsSerine EndopeptidasesViral Nonstructural ProteinsViral Proteases

Identifiers

PMID24164286
PMCPMC3923078
OpenAlexW2041674831

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.