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doi:10.22028/D291-41997
Titel: | Near-Neighbor Interactions in the NS3-4A Protease of HCV Impact Replicative Fitness of Drug-Resistant Viral Variants |
VerfasserIn: | Doncheva, Nadezhda T. Domingues, Francisco S. McGivern, David R Shimakami, Tetsuro Zeuzem, Stefan Lengauer, Thomas Lange, Christian M. Albrecht, Mario Welsch, Christoph |
Sprache: | Englisch |
Titel: | Journal of Molecular Biology |
Bandnummer: | 431 |
Heft: | 12 |
Seiten: | 2354-2368 |
Verlag/Plattform: | Elsevier |
Erscheinungsjahr: | 2019 |
Freie Schlagwörter: | hepatitis C virus subtype viral variant fitness residue networks molecular determinants |
DDC-Sachgruppe: | 004 Informatik |
Dokumenttyp: | Journalartikel / Zeitschriftenartikel |
Abstract: | A variety of amino acid substitutions in the NS3-4A protease of the hepatitis C virus lead to protease inhibitor (PI) resistance. Many of these significantly impair the replication fitness of the resistant variants in a genotype- and subtype-dependent manner, a critical factor in determining the probability with which resistant variants will persist. However, the underlying molecular mechanisms are unknown. Here, we present a novel residue interaction network approach to determine how near-neighbor interactions of PI resistance mutations in NS3-4A can impact protease functional sites dependent on their genomic background. We constructed subtype-specific consensus residue networks for subtypes 1a and 1b from protease structure ensembles combined with biological properties of protein residues and evolutionary amino acid conservation. By applying local and global network topology analysis and visual exploration, we characterize PI resistance-associated sites and outline differences in near-neighbor interactions. We find local residue-interaction patterns and features at protease functional sites that are subtype specific. The noncovalent bonding patterns indicate higher fitness costs conferred by PI resistance mutations in a subtype 1b genomic background and explain the prevalence of Q80K and R155K in subtype 1a. Based on local residue interactions, we predict a subtype-specific role for the protease residue NS3–Q80 in molecular mechanisms related to the assembly of infectious virus particles that is supported by experimental data on the capacity of Q80K variants to replicate and produce infectious virus in subtype 1a and 1b cell culture. |
DOI der Erstveröffentlichung: | 10.1016/j.jmb.2019.04.034 |
URL der Erstveröffentlichung: | https://doi.org/10.1016/j.jmb.2019.04.034 |
Link zu diesem Datensatz: | urn:nbn:de:bsz:291--ds-419971 hdl:20.500.11880/37583 http://dx.doi.org/10.22028/D291-41997 |
ISSN: | 0022-2836 |
Datum des Eintrags: | 6-Mai-2024 |
Bezeichnung des in Beziehung stehenden Objekts: | Supplementary data |
In Beziehung stehendes Objekt: | https://ars.els-cdn.com/content/image/1-s2.0-S0022283619302426-mmc1.docx https://ars.els-cdn.com/content/image/1-s2.0-S0022283619302426-mmc2.xls |
Fakultät: | MI - Fakultät für Mathematik und Informatik |
Fachrichtung: | MI - Informatik |
Professur: | MI - Keiner Professur zugeordnet |
Sammlung: | SciDok - Der Wissenschaftsserver der Universität des Saarlandes |
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