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>