Deciphering the ATP-binding mechanism(s) in NLRP-NACHT 3D models using structural bioinformatics approaches

Area of Science:

• Immunology
• Structural Biology
• Computational Biology

Background:

• Nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) are cytosolic pattern recognition receptors crucial for innate immunity.
• NLRs, part of the AAA+ ATPase superfamily, regulate inflammatory responses but their signaling mechanisms, including nucleotide binding, are not fully understood due to limited structural data.
• Understanding NLRP function is vital for controlling inflammatory diseases.

Purpose of the Study:

• To investigate the structural and dynamic features of ADP-/ATP-Mg2+ binding in NLRPNACHT domains using computational methods.
• To elucidate the conserved mechanisms of nucleotide binding within the NLRPNACHT protein family.
• To identify key residues involved in ATP coordination for potential therapeutic targeting.

Main Methods:

• Protein modeling to generate NLRPNACHT structural models.
• Molecular docking to predict binding modes of ADP/ATP-Mg2+.
• Molecular dynamics simulations to analyze binding stability and interactions over time.

Main Results:

• A conserved mode of ATP-Mg2+ binding was identified across all modeled NLRPNACHT proteins.
• Key interacting residues involved in ATP-Mg2+ coordination were consistent with experimental mutagenesis data.
• Additional conserved residues, including those in the PhhCW and GFxxxxRxxYF motifs, were implicated in ATP binding during molecular dynamics simulations.

Conclusions:

• The study provides insights into the conserved ADP-/ATP-Mg2+ binding mechanisms in NLRPs.
• Identified conserved residues and the ATP-binding pocket offer potential targets for designing novel inhibitors of inflammasome activity.
• Further experimental validation is needed for the newly proposed interacting residues.