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Articles 1 - 4 of 4

Full-Text Articles in Molecular Biology

Resistance From Afar: Distal Mutation V36m Allosterically Modulates The Active Site To Accentuate Drug Resistance In Hcv Ns3/4a Protease, Aysegul Ozen, Kuan-Hung Lin, Keith P. Romano, Davide Tavella, Alicia Newton, Christos J. Petropoulos, Wei Huang, Cihan Aydin, Celia A. Schiffer Dec 2018

Resistance From Afar: Distal Mutation V36m Allosterically Modulates The Active Site To Accentuate Drug Resistance In Hcv Ns3/4a Protease, Aysegul Ozen, Kuan-Hung Lin, Keith P. Romano, Davide Tavella, Alicia Newton, Christos J. Petropoulos, Wei Huang, Cihan Aydin, Celia A. Schiffer

University of Massachusetts Medical School Faculty Publications

Hepatitis C virus rapidly evolves, conferring resistance to direct acting antivirals. While resistance via active site mutations in the viral NS3/4A protease has been well characterized, the mechanism for resistance of non-active site mutations is unclear. R155K and V36M often co-evolve and while R155K alters the electrostatic network at the binding site, V36M is more than 13 Angstrom away. In this study the mechanism by which V36M confers resistance, in the context of R155K, is elucidated with drug susceptibility assays, crystal structures, and molecular dynamics (MD) simulations for three protease inhibitors: telaprevir, boceprevir and danoprevir. The R155K and R155K ...


Primate Immunodeficiency Virus Vpx And Vpr Counteract Transcriptional Repression Of Proviruses By The Hush Complex, Leonid Yurkovetskiy, Mehmet Hakan Guney, Kyusik Kim, Shih Lin Goh, Sean M. Mccauley, Ann Dauphin, William E. Diehl, Jeremy Luban Apr 2018

Primate Immunodeficiency Virus Vpx And Vpr Counteract Transcriptional Repression Of Proviruses By The Hush Complex, Leonid Yurkovetskiy, Mehmet Hakan Guney, Kyusik Kim, Shih Lin Goh, Sean M. Mccauley, Ann Dauphin, William E. Diehl, Jeremy Luban

University of Massachusetts Medical School Faculty Publications

Drugs that inhibit HIV-1 replication and prevent progression to AIDS do not eliminate HIV-1 proviruses from the chromosomes of long-lived CD4+ memory T cells. To escape eradication by these antiviral drugs, or by the host immune system, HIV-1 exploits poorly defined host factors that silence provirus transcription. These same factors, though, must be overcome by all retroviruses, including HIV-1 and other primate immunodeficiency viruses, in order to activate provirus transcription and produce new virus. Here we show that Vpx and Vpr, proteins from a wide range of primate immunodeficiency viruses, activate provirus transcription in human CD4+ T cells. Provirus activation ...


Prima: A Gene-Centered, Rna-To-Protein Method For Mapping Rna-Protein Interactions, Alex M. Tamburino, Ebru Kaymak, Shaleen Shrestha, Amy D. Holdorf, Sean P. Ryder, Albertha J. M. Walhout Sep 2016

Prima: A Gene-Centered, Rna-To-Protein Method For Mapping Rna-Protein Interactions, Alex M. Tamburino, Ebru Kaymak, Shaleen Shrestha, Amy D. Holdorf, Sean P. Ryder, Albertha J. M. Walhout

University of Massachusetts Medical School Faculty Publications

Interactions between RNA binding protein (RBP) and mRNAs are critical to post-transcriptional gene regulation. Eukaryotic genomes encode thousands of mRNAs and hundreds of RBPs. However, in contrast to interactions between transcription factors (TFs) and DNA, the interactome between RBPs and RNA has been explored for only a small number of proteins and RNAs. This is largely because the focus has been on using 'protein-centered' (RBP-to-RNA) interaction mapping methods that identify the RNAs with which an individual RBP interacts. While powerful, these methods cannot as of yet be applied to the entire RBPome. Moreover, it may be desirable for a researcher ...


A Systematic Survey Of An Intragenic Epistatic Landscape, Claudia Bank, Ryan T. Hietpas, Jeffrey D. Jensen, Daniel N. Bolon Oct 2014

A Systematic Survey Of An Intragenic Epistatic Landscape, Claudia Bank, Ryan T. Hietpas, Jeffrey D. Jensen, Daniel N. Bolon

University of Massachusetts Medical School Faculty Publications

Mutations are the source of evolutionary variation. The interactions of multiple mutations can have important effects on fitness and evolutionary trajectories. We have recently described the distribution of fitness effects of all single mutations for a nine amino acid region of yeast Hsp90 (Hsp82) implicated in substrate binding. Here, we report and discuss the distribution of intragenic epistatic effects within this region in seven Hsp90 point mutant backgrounds of neutral to slightly deleterious effect, resulting in an analysis of more than 1000 double-mutants. We find negative epistasis between substitutions to be common, and positive epistasis to be rare – resulting in ...