Journal Article

Discovery of a hidden transient state in all bromodomain families

Christ, Clara D., Noé, Frank, Raich, Lluís, Olsson, Simon, Meier, Katharina, Günther, Judith

2021

Overview

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.

• Publisher: National Academy of Sciences
• Subject: allosteric effects / Amino Acid Sequence / Binding Sites / Biophysics and Computational Biology / bromodomains / Cell Cycle Proteins - chemistry / Cell Cycle Proteins - genetics / Cell Cycle Proteins - metabolism / Co-Repressor Proteins - chemistry / Co-Repressor Proteins - genetics / Co-Repressor Proteins - metabolism / cryptic pockets / Crystallography, X-Ray / DNA - chemistry / DNA - genetics / DNA - metabolism / DNA-Binding Proteins - chemistry / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Gene Expression Regulation / Histone Acetyltransferases - chemistry / Histone Acetyltransferases - genetics / Histone Acetyltransferases - metabolism / Humans / Intracellular Signaling Peptides and Proteins - chemistry / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - metabolism / Markov Chains / Markov models / minor conformational states / Molecular Dynamics Simulation / Physical Sciences / Protein Binding / Protein Conformation, alpha-Helical / Protein Conformation, beta-Strand / Protein Interaction Domains and Motifs / Sequence Alignment / Sequence Homology, Amino Acid / Thermodynamics / Transcription Factors - chemistry / Transcription Factors - genetics / Transcription Factors - metabolism / Transcription Factors, General - chemistry / Transcription Factors, General - genetics / Transcription Factors, General - metabolism / Tripartite Motif-Containing Protein 28 - chemistry / Tripartite Motif-Containing Protein 28 - genetics / Tripartite Motif-Containing Protein 28 - metabolism