Structural study of a small molecule receptor bound to dimethyllysine in lysozyme

Area of Science:

• Biochemistry
• Structural Biology
• Chemical Biology

Background:

• Lysine residues are crucial on protein surfaces and undergo post-translational methylation.
• Methylated lysines (mono-, di-, or trimethylated) significantly alter protein interactions and signaling pathways.
• Targeting methylated lysines with small molecules offers a route to modulate these pathways.

Purpose of the Study:

• To determine the detailed structural basis of small molecule interaction with methylated lysine.
• To investigate the binding of p-sulfonatocalix[4]arene (sclx4) to chemically dimethylated lysozyme.
• To provide structural insights for the development of novel biochemical reagents targeting methylated lysines.

Main Methods:

• X-ray crystallography to determine the complex structure of sclx4 and dimethylated lysozyme.
• Chemical modification of lysine residues to dimethyllysine (Lys-Me2).
• Nuclear Magnetic Resonance (NMR) spectroscopy and Molecular Dynamics (MD) simulations for solution-state validation.

Main Results:

• The crystal structure revealed sclx4 selectively binding to Lys116-Me2 on lysozyme.
• The dimethylamino group of Lys116-Me2 was observed to be deeply embedded within the calixarene cavity.
• The binding interaction was confirmed to involve cation-π interactions, consistent with known protein recognition of methylated lysine.
• NMR and MD simulations supported the selectivity for Lys116-Me2 in solution.

Conclusions:

• The reported crystal structure provides a detailed molecular understanding of sclx4 binding to dimethylated lysine.
• The findings validate the role of cation-π interactions in recognizing methylated lysine residues.
• This structural data serves as a foundation for designing new chemical tools to target methylated lysine modifications.