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Understanding the Molecular Differential Recognition of Muramyl Peptide Ligands by LRR Domains of Human NOD Receptors.

Publication Type : Journal Article

Thematic Areas : Medical Sciences, Nanosciences and Molecular Medicine

Publisher : Biochem J

Source : Biochem J, Volume 474, Issue 16, p.2691-2711 (2017)

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Keywords : Acetylmuramyl-Alanyl-Isoglutamine, HEK293 Cells, Humans, Ligands, Molecular Docking Simulation, Nod1 Signaling Adaptor Protein, Nod2 Signaling Adaptor Protein, Protein Domains

Campus : Kochi

School : Center for Nanosciences, School of Medicine

Center : Amrita Center for Nanosciences and Molecular Medicine Move, Nanosciences

Department : Microbiology, Nanosciences and Molecular Medicine

Year : 2017

Abstract : Human nucleotide-binding oligomerization domain proteins, hNOD1 and hNOD2, are host intracellular receptors with C-terminal leucine-rich repeat (LRR) domains, which recognize specific bacterial peptidoglycan (PG) fragments as their ligands. The specificity of this recognition is dependent on the third amino acid of the stem peptide of the PG ligand, which is usually -diaminopimelic acid (DAP) or l-lysine (l-Lys). Since the LRR domains of hNOD receptors had been experimentally shown to confer the PG ligand-sensing specificity, we developed three-dimensional structures of hNOD1-LRR and the hNOD2-LRR to understand the mechanism of differential recognition of muramyl peptide ligands by hNOD receptors. The hNOD1-LRR and hNOD2-LRR receptor models exhibited right-handed curved solenoid shape. The hot-spot residues experimentally proved to be critical for ligand recognition were located in the concavity of the NOD-LRR and formed the recognition site. Our molecular docking analyses and molecular electrostatic potential mapping studies explain the activation of hNOD-LRRs, in response to effective molecular interactions of PG ligands at the recognition site; and conversely, the inability of certain PG ligands to activate hNOD-LRRs, by deviations from the recognition site. Based on molecular docking studies using PG ligands, we propose few residues - G825, D826 and N850 in hNOD1-LRR and L904, G905, W931, L932 and S933 in hNOD2-LRR, evolutionarily conserved across different host species, which may play a major role in ligand recognition. Thus, our integrated experimental and computational approach elucidates the molecular basis underlying the differential recognition of PG ligands by hNOD receptors.

Cite this Research Publication : S. Vijayrajratnam, Pushkaran, A. Choorakott, Balakrishnan, A., Vasudevan, A. Kumar, Dr. Raja Biswas, and Dr. Gopi Mohan C., “Understanding the Molecular Differential Recognition of Muramyl Peptide Ligands by LRR Domains of Human NOD Receptors.”, Biochem J, vol. 474, no. 16, pp. 2691-2711, 2017.

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