title: Structural models of zebrafish (Danio rerio) NOD1 and NOD2 NACHT domains suggest differential ATP binding orientations: insights from computational modeling, docking and molecular dynamics simulations.
abstract: Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) and NOD2 are cytosolic pattern recognition receptors playing pivotal roles in innate immune signaling. NOD1 and NOD2 recognize bacterial peptidoglycan derivatives iE-DAP and MDP, respectively and undergoes conformational alternation and ATP-dependent self-oligomerization of NACHT domain followed by downstream signaling. Lack of structural adequacy of NACHT domain confines our understanding about the NOD-mediated signaling mechanism. Here, we predicted the structure of NACHT domain of both NOD1 and NOD2 from model organism zebrafish (Danio rerio) using computational methods. Our study highlighted the differential ATP binding modes in NOD1 and NOD2. In NOD1, γ-phosphate of ATP faced toward the central nucleotide binding cavity like NLRC4, whereas in NOD2 the cavity was occupied by adenine moiety. The conserved 'Lysine' at Walker A formed hydrogen bonds (H-bonds) and Aspartic acid (Walker B) formed electrostatic interaction with ATP. At Sensor 1, Arg328 of NOD1 exhibited an H-bond with ATP, whereas corresponding Arg404 of NOD2 did not. 'Proline' of GxP motif (Pro386 of NOD1 and Pro464 of NOD2) interacted with adenine moiety and His511 at Sensor 2 of NOD1 interacted with γ-phosphate group of ATP. In contrast, His579 of NOD2 interacted with the adenine moiety having a relatively inverted orientation. Our findings are well supplemented with the molecular interaction of ATP with NLRC4, and consistent with mutagenesis data reported for human, which indicates evolutionary shared NOD signaling mechanism. Together, this study provides novel insights into ATP binding mechanism, and highlights the differential ATP binding modes in zebrafish NOD1 and NOD2.
authors: Department of Bioinformatics, Orissa University of Agriculture and Technology,Bhubaneswar, Odisha, India; Biotechnology Laboratory, ICAR-Central Inland Fisheries Research Institute, Barrackpore, Kolkata, West Bengal, India.
authors: Jitendra
authors: J
authors: Maharana
authors: Department of Bioinformatics, Orissa University of Agriculture and Technology,Bhubaneswar, Odisha, India.
authors: Bikash Ranjan
authors: BR
authors: Sahoo
authors: Department of Bioinformatics, Orissa University of Agriculture and Technology,Bhubaneswar, Odisha, India.
authors: Aritra
authors: A
authors: Bej
authors: Department of Bioinformatics, Orissa University of Agriculture and Technology,Bhubaneswar, Odisha, India.
authors: Itishree
authors: I
authors: Jena
authors: Department of Bioinformatics, Orissa University of Agriculture and Technology,Bhubaneswar, Odisha, India.
authors: Arunima
authors: A
authors: Parida
authors: Department of Bioinformatics, Orissa University of Agriculture and Technology,Bhubaneswar, Odisha, India.
authors: Jyoti Ranjan
authors: JR
authors: Sahoo
authors: Biomedical Informatics Centre, Regional Medical Research Institute (ICMR), Bhubaneswar, Odisha, India.
authors: Budheswar
authors: B
authors: Dehury
authors: Department of Bioinformatics, Orissa University of Agriculture and Technology,Bhubaneswar, Odisha, India.
authors: Mahesh Chandra
authors: MC
authors: Patra
authors: Department of Bioinformatics, Orissa University of Agriculture and Technology,Bhubaneswar, Odisha, India.
authors: Sushma Rani
authors: SR
authors: Martha
authors: Department of Bioinformatics, Orissa University of Agriculture and Technology,Bhubaneswar, Odisha, India.
authors: Sucharita
authors: S
authors: Balabantray
authors: Department of Bioinformatics, Orissa University of Agriculture and Technology,Bhubaneswar, Odisha, India.
authors: Sukanta Kumar
authors: SK
authors: Pradhan
authors: Biotechnology Laboratory, ICAR-Central Inland Fisheries Research Institute, Barrackpore, Kolkata, West Bengal, India.
authors: Bijay Kumar
authors: BK
authors: Behera
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D006860:Hydrogen Bonding; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D053474:Nod1 Signaling Adaptor Protein / Q000737:chemistry* / Q000378:metabolism*; D053473:Nod2 Signaling Adaptor Protein / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D015203:Reproducibility of Results; D016415:Sequence Alignment; D015027:Zebrafish
chemical_list: D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D000255:Adenosine Triphosphate