Discovery of a hidden transient state in all bromodomain families
Artikel i vetenskaplig tidskrift, 2021

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 alpha(A) 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.

allosteric effects


cryptic pockets

Markov models

minor conformational states


Lluis Raich

Freie Universität Berlin

Katharina Meier

Bayer AG

Judith Guenther

Bayer AG

Clara D. Christ

Bayer AG

Frank Noe

Freie Universität Berlin

Rice University

Simon Olsson

Freie Universität Berlin

Chalmers, Data- och informationsteknik, Data Science

Proceedings of the National Academy of Sciences of the United States of America

0027-8424 (ISSN) 1091-6490 (eISSN)

Vol. 118 4 e2017427118




Bioinformatik och systembiologi





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