Discovery of a hidden transient state in all bromodomain families.
Proc Natl Acad Sci U S A
; 118(4)2021 01 26.
Article
em En
| MEDLINE
| ID: mdl-33468647
ABSTRACT
Bromodomains (BDs) are small protein modules that interact with acetylated marks in histones. These posttranslational modifications are pivotal to regulate gene expression, making BDs promising targets to treat several diseases. While the general structure of BDs is well known, their dynamical features and their interplay with other macromolecules are poorly understood, hampering the rational design of potent and selective inhibitors. Here, we combine extensive molecular dynamics simulations, Markov state modeling, and available structural data to reveal a transiently formed state that is conserved across all BD families. It involves the breaking of two backbone hydrogen bonds that anchor the ZA-loop with the αA helix, opening a cryptic pocket that partially occludes the one associated to histone binding. By analyzing more than 1,900 experimental structures, we unveil just two adopting the hidden state, explaining why it has been previously unnoticed and providing direct structural evidence for its existence. Our results suggest that this state is an allosteric regulatory switch for BDs, potentially related to a recently unveiled BD-DNA-binding mode.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
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Proteínas de Ciclo Celular
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Fatores Genéricos de Transcrição
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Peptídeos e Proteínas de Sinalização Intracelular
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Proteínas de Ligação a DNA
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Histona Acetiltransferases
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Proteínas Correpressoras
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Proteína 28 com Motivo Tripartido
Tipo de estudo:
Health_economic_evaluation
/
Prognostic_studies
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Alemanha