Structural basis of LSD1-CoREST selectivity in histone H3 recognition.

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Histone demethylase Lysine-specific demethylase 1 (LSD1) is a key epigenetic regulator controlling gene transcription.
• LSD1 removes the methyl mark from histone H3 at lysine 4 (Lys4), influencing chromatin structure and gene expression.
• The interaction with its cofactor CoREST is essential for LSD1's activity and substrate recognition.

Purpose of the Study:

• To determine the crystal structure of LSD1 in complex with CoREST and a substrate-like peptide inhibitor.
• To elucidate the molecular interactions governing substrate binding and catalytic activity.
• To understand the structural basis for LSD1's substrate specificity and the role of CoREST.

Main Methods:

• X-ray crystallography was employed to obtain the high-resolution structure of the LSD1-CoREST-inhibitor complex.
• Analysis of the three-dimensional structure to identify key amino acid residues and interactions.
• Computational modeling to predict substrate binding and catalytic mechanisms.

Main Results:

• The crystal structure reveals a folded conformation of the bound peptide inhibitor, stabilized by intramolecular hydrogen bonds.
• Specific electrostatic interactions between charged residues in the LSD1 binding pocket and the peptide were identified.
• The structure predicts that the methylated Lys4 of histone H3 binds in a protected active site, positioned for flavin-mediated oxidation.

Conclusions:

• The intricate network of interactions and the enzyme's architecture explain LSD1's high substrate specificity.
• The structural data provide a framework for understanding the catalytic mechanism of demethylation via flavin-dependent oxidation.
• CoREST plays an active role in substrate recognition, contributing to the fine-tuning of LSD1's catalytic activity.