10.1371/journal.pone.0209420 Jitendra Maharana Jitendra Maharana Debashis Panda Debashis Panda Sachinandan De Sachinandan De Deciphering the ATP-binding mechanism(s) in NLRP-NACHT 3D models using structural bioinformatics approaches Public Library of Science 2018 ATP-Mg oligomerization domain NLRP-signaling mechanism ATPase superfamily PRR inflammasome activity sensor-adaptor-effector interactions C-terminal end novel inhibitors NLRP NACHT models residue ATP-binding pocket NLRP-NACHT 3 D models NOD LRR cytosolic pattern recognition receptors bioinformatics approaches ADP mutagenesis data protein modeling AAA pathogen recognition bioinformatics approaches Nucleotide-binding EBD PhhC W motif dynamics simulations G F xxxxRxx Y F motif structural-dynamic features 2018-12-20 18:34:17 Dataset https://plos.figshare.com/articles/dataset/Deciphering_the_ATP-binding_mechanism_s_in_NLRP-NACHT_3D_models_using_structural_bioinformatics_approaches/7493483 <div><p>Nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs), the first line of defense, are the cytosolic pattern recognition receptors (PRRs) that regulate the inflammatory activity in response to invading pathogens. NLRs are the members of AAA+ ATPase superfamily that comprises of N-terminal EBD(s), a centrally positioned NOD/NACHT and varying range of LRRs towards the C-terminal end. Due to the lack of structural data, the functional aspects of NLRP-signaling mechanism, which includes pathogen recognition, nucleotide-binding, and sensor-adaptor-effector interactions, are not fully understood. In this study, we implemented structural bioinformatics approaches including protein modeling, docking, and molecular dynamics simulations to explore the structural-dynamic features of ADP-/ATP-Mg<sup>2+</sup> binding in NLRP<sup>NACHT</sup> models. Our results indicate a similar mode of ATP-Mg<sup>2+</sup> binding in all NLRP<sup>NACHT</sup> models and the interacting residues are found consistent with reported mutagenesis data. Accompanied by the key amino acids (proposed to be crucial for ATP-Mg<sup>2+</sup> coordination), we further have noticed that some additional conserved residues (including ‘Trp’ of the PhhC<u>W</u> motif, and ‘Phe’ and ‘Tyr’ of the G<u>F</u>xxxxRxx<u>Y</u>F motif) are potentially interacting with ATP during dynamics; which require further experimentation for legitimacy. Overall, this study will help in understanding the ADP-/ATP-Mg<sup>2+</sup> binding mechanisms in NLRPs in a broader perspective and the proposed ATP-binding pocket will aid in designing novel inhibitors for the regulation of inflammasome activity.</p></div>