Loop Plasticity Drives Paralog-Specific Recognition in BET ET Domains

Area of Science:

• Molecular biology
• Structural biology
• Biophysics

Background:

• Bromodomain and extraterminal domain (BET) proteins bind diverse peptides through conserved ET domains.
• Paralog-specific binding preferences of BET proteins lack clear structural explanations.

Purpose of the Study:

• Investigate the structural basis for paralog-specific peptide recognition by BRD3 and BRD4 ET domains.
• Analyze interactions with peptide binders from NSD3 and murine leukemia virus integrase.

Main Methods:

• Extensive molecular dynamics simulations.
• Ensemble-based analyses.
• Computational biophysics techniques.

Main Results:

• Peptide recognition differences arise from subtle loop dynamics and local secondary structure variations, not large conformational changes.
• Two divergent residues (positions 35 and 36) in a flexible loop modulate flanking helix formation and peptide-binding cavity opening.
• BRD3 exhibits greater conformational plasticity and weaker binding, especially for NSD3, compared to BRD4.

Conclusions:

• Local sequence variations fine-tune the conformational ensemble of BET ET domains.
• These dynamics influence binding modes through conformational selection and induced fit mechanisms.
• Provides a structural basis for the paralog-specific targeting of BET proteins.