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Effect of BET missense mutations on bromodomain function, inhibitor binding and stability

TitoloEffect of BET missense mutations on bromodomain function, inhibitor binding and stability
Tipo di pubblicazioneArticolo su Rivista peer-reviewed
Anno di Pubblicazione2016
AutoriLori, L., Pasquo A., Lori C., Petrosino M., Chiaraluce R., Tallant C., Knapp S., and Consalvi V.
RivistaPLoS ONE
Volume11
ISSN19326203
Parole chiaveacetic acid derivative, Amino Acid Sequence, amino acid substitution, antagonists and inhibitors, article, binding affinity, binding site, bromo and extra terminal protein, carrier proteins and binding proteins, chemistry, conformation, controlled study, Crystal structure, genetics, lysine, metabolism, Missense, missense mutation, Models, Molecular, molecular model, mutation, mutational analysis, Neoplasm Proteins, protein binding, protein domain, Protein Domains, protein protein interaction, protein stability, structure activity relation, structure analysis, tumor protein, unclassified drug
Abstract

Lysine acetylation is an important epigenetic mark regulating gene transcription and chromatin structure. Acetylated lysine residues are specifically recognized by bromodomains, small protein interaction modules that read these modification in a sequence and acetylation dependent way regulating the recruitment of transcriptional regulators and chromatin remodelling enzymes to acetylated sites in chromatin. Recent studies revealed that bromodomains are highly druggable protein interaction domains resulting in the development of a large number of bromodomain inhibitors. BET bromodomain inhibitors received a lot of attention in the oncology field resulting in the rapid translation of early BET bromodomain inhibitors into clinical studies. Here we investigated the effects of mutations present as polymorphism or found in cancer on BET bromodomain function and stability and the influence of these mutants on inhibitor binding. We found that most BET missense mutations localize to peripheral residues in the two terminal helices. Crystal structures showed that the three dimensional structure is not compromised by these mutations but mutations located in close proximity to the acetyl-lysine binding site modulate acetyl-lysine and inhibitor binding. Most mutations affect significantly protein stability and tertiary structure in solution, suggesting new interactions and an alternative network of protein-protein interconnection as a consequence of single amino acid substitution. To our knowledge this is the first report studying the effect of mutations on bromodomain function and inhibitor binding. © 2016 Lori et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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cited By 8

URLhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-84978884260&doi=10.1371%2fjournal.pone.0159180&partnerID=40&md5=02970afb7dc919be3d3287e5a4911fc1
DOI10.1371/journal.pone.0159180
Citation KeyLori2016