Linked Life Data

10966782

Source:http://linkedlifedata.com/resource/pubmed/id/10966782

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2000-9-21
pubmed:abstractText
Dengue viruses are members of the Flaviviridae and cause dengue fever and the more severe dengue hemorrhagic fever. Although nearly 40 % of the world's population is at risk of dengue infection, there is currently no effective vaccine or chemotherapy for the disease. Processing of the dengue polyprotein into structural and non-structural proteins in a host, which is essential for assembly of infective virions, is carried out by the combined action of host proteases and the trypsin-like, two-component viral NS2B/NS3 serine protease. Although NS2B strongly stimulates the catalytic NS3 protease domain, the latter is fully active against small substrates and possesses detectable activity against larger substrates, making both forms of the enzyme possible targets for drug design. In the crystal structure of a complex of the protease with a Bowman-Birk inhibitor reported here, an Arg residue at the P1 position of the inhibitor is bound in a manner distinctly different from that in other serine proteases of comparable specificity. However, because the regulatory component, NS2B, is not present in the complex, the physiological implications of this observations are currently unclear. The redundant nature of interaction of P1 Arg and Lys residues with Asp129, Tyr150 and Ser163 of the enzyme provides an explanation for the observed behavior of several site-specific mutants of Asp129 in the protease. The strong level of conservation of residues in the protease that interact with the P1 Arg, along with conservation of Arg at P1 of most cleavage sites in other flaviviruses, suggests that observations from this structure are likely to be applicable to many flaviviruses. The structure provides a starting point for design of site-specific mutations to probe the mechanism of catalysis by the catalytic domain, its activation by the regulatory domain and for design of specific inhibitors of enzymatic activity.
pubmed:commentsCorrections
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0022-2836
pubmed:author
pubmed:copyrightInfo
Copyright 2000 Academic Press.
pubmed:issnType
Print
pubmed:day
25
pubmed:volume
301
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
759-67
pubmed:dateRevised
2010-4-5
pubmed:meshHeading
pubmed-meshheading:10966782-Catalytic Domain, pubmed-meshheading:10966782-Crystallography, X-Ray, pubmed-meshheading:10966782-Dengue Virus, pubmed-meshheading:10966782-Drug Design, pubmed-meshheading:10966782-Enzyme Inhibitors, pubmed-meshheading:10966782-Ligands, pubmed-meshheading:10966782-Models, Molecular, pubmed-meshheading:10966782-Mutation, pubmed-meshheading:10966782-Polyproteins, pubmed-meshheading:10966782-Protein Conformation, pubmed-meshheading:10966782-Protein Processing, Post-Translational, pubmed-meshheading:10966782-RNA Helicases, pubmed-meshheading:10966782-Serine Endopeptidases, pubmed-meshheading:10966782-Substrate Specificity, pubmed-meshheading:10966782-Trypsin Inhibitor, Bowman-Birk Soybean, pubmed-meshheading:10966782-Viral Nonstructural Proteins, pubmed-meshheading:10966782-Viral Proteins
pubmed:year
2000
pubmed:articleTitle
Crystal structure of Dengue virus NS3 protease in complex with a Bowman-Birk inhibitor: implications for flaviviral polyprotein processing and drug design.
pubmed:affiliation
Center for Macromolecular Crystallography, University of Alabama at Birmingham, 1918 University Boulevard, 79 THT MCLM 244, Birmingham, AL, 35294-0005, USA. murthy@onyx.cmc.uab.edu
pubmed:publicationType
Journal Article, Retracted Publication