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Not AvailableScrutinizing various nucleotide-binding oligomerization domain (NOD)-like receptors (NLR) genes in higher eukaryotes is very important for understanding the intriguing mechanism of host defense against pathogens. The nucleotide-binding domain (NACHT), leucine-rich repeat (LRR) and pyrin domain (PYD) containing protein 3 (Nalp3) is an intracellular innate immune receptor, and is associated with several immune system related disorders. Despite of Nalp3’s protective role during pathogenic invasion, the molecular feature, and structural organization of this crucial protein is poorly understood. Using comparative modeling and molecular dynamics simulations, we have studied the structural architecture of Nalp3 domains, and characterized the dynamic and energetic parameters of adenosine triphosphate (ATP) binding in NACHT and pathogen derived ligands muramyl dipeptide (MDP) and imidazoquinoline with LRR domains. The results anticipated walker A, B and extended walker B motifs as the key ATP binding regions in NACHT that mediates self-oligomerization. Analysis of binding sites of MDP and imidazoquinoline revealed LRR7-9 being the most energetically favored site of imidazoquinoline interaction. However, binding free energy calculations using Molecular Mechanics/Possion-Boltzman Surface Area (MM/PBSA) method advocated that MDP is incompatible for activating Nalp3 molecule in monomeric form and suggest its complex nature with NOD2 or other NLRs for MDP recognition. The high binding affinity of ATP with NACHT is correlated to the experimental data for human NLRs. Our binding site prediction for imidazoquinoline in LRR warrants further investigation via in vivo models. This is the first study that provides ligand(s) recognition in mouse Nalp3 and its spatial structural arrangements.Not Availabl

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Not AvailableNucleotide binding and oligomerization domain 1 (NOD1), a cytoplasmic pattern recognition receptor (PRR) and is a key component for modulating innate immunity and signaling. It is highly specific to γ-D-Glu-mDAP (iE-DAP), a cell wall component of Gram-negative and few Gram-positive bacteria. In the absence of the experimental structure of NOD1 leucine rich repeat (NOD1-LRR) domain, the NOD signaling cascade mediated through NOD1 and iE-DAP interaction is poorly understood. Herein, we modeled 3D structure of zebrafish NOD1-LRR (zNOD1-LRR) through a protein-threading approach and structural integrity of the model was assessed using molecular dynamics simulations. Molecular interaction analysis of iE-DAP and zNOD1-LRR, their complex stability and binding free energy studies were conducted to anticipate the ligand binding residues in zNOD1. Our study revealed that His775, Lys777, Asp803, Gly805, Trp807, Asn831, Ser833, Ile859 and Trp861 situated in the β-sheet region of zNOD1-LRR could be involved in iE-DAP recognition, which correlates the earlier findings in human. Comparison of binding free energies of native and mutant zNOD1-iE-DAP complexes delineated His775, Lys777, Asp803, Ser833 and Ile859 as the pivotal residues for energetic stability of NOD1 and iE-DAP interaction. This study provides the first comprehensive description of biophysical and biochemical parameters responsible for NOD1 and iE-DAP interaction in zebrafish, which is expected to shed more light on NOD1 signaling and therapeutic applications in other organisms.Not Availabl