title: Molecular modeling and structural analysis of nAChR variants uncovers the mechanism of resistance to snake toxins.
abstract: Nicotinic acetylcholine receptors (nAChRs) are neuromuscular proteins responsible for muscle contraction upon binding with chemical stimulant acetylcholine (ACh). The α-neurotoxins of snake mimic the structure of ACh and attacks nAChRs, which block the flow of ACh and leads to numbness and paralysis. The toxin-binding site of alpha subunit in the nAChRs is highly conserved throughout chordate lineages with few exceptions in resistance organisms. In this study, we have analyzed the sequence and structures of toxin-binding/resistant nAChRs and their interaction stability with toxins through molecular docking and molecular dynamics simulation (MDS). We have reported the potential glycosylation residues within the toxin-binding cleft adding sugar moieties through N-linked glycosylation in resistant organisms. Residue variations at key positions alter the secondary structure of binding cleft, which might interfere with toxin binding and it could be one of the possible explanations for the resistance to snake venoms. Analysis of nAChR-α-neurotoxin complexes has confirmed the key interacting residues. In addition, drastic variation in the binding stability of Mongoose nAChR-α-Bungarotoxin (α-BTX) and human nAChR-α-BTX complexes were found at specific phase of MDS. Our findings suggest that specific mutations in the binding site of toxin are potentially preventing the formation of stable complex of receptor-toxin, which might lead to mechanism of resistance. This in silico study on the binding cleft of nAChR and the findings of interacting residues will assist in designing potential inhibitors as therapeutic targets.
authors.affiliation: a UGC-Networking Resource Centre in Biological Sciences, School of Biological Sciences , Madurai Kamaraj University , Madurai 625021 , India.
authors.forename: D
authors.initials: D
authors.lastname: Gunasekaran
authors.affiliation: a UGC-Networking Resource Centre in Biological Sciences, School of Biological Sciences , Madurai Kamaraj University , Madurai 625021 , India.|b Department of Biotechnology (DDE) , Madurai Kamaraj University , Madurai 625021 , India.
authors.forename: J
authors.initials: J
authors.lastname: Sridhar
authors.affiliation: c Computer Aided Drug Design and Molecular Modelling Lab, Department of Bioinformatics , Alagappa University , Karaikudi 630003 , Tamil Nadu , India.
authors.forename: V
authors.initials: V
authors.lastname: Suryanarayanan
authors.affiliation: a UGC-Networking Resource Centre in Biological Sciences, School of Biological Sciences , Madurai Kamaraj University , Madurai 625021 , India.
authors.forename: N C
authors.initials: NC
authors.lastname: Manimaran
authors.affiliation: c Computer Aided Drug Design and Molecular Modelling Lab, Department of Bioinformatics , Alagappa University , Karaikudi 630003 , Tamil Nadu , India.
authors.forename: Sanjeev Kumar
authors.initials: SK
authors.lastname: Singh
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002038:Bungarotoxins / Q000737:chemistry* / Q000378:metabolism; D017812:Colubridae / Q000502:physiology; D018360:Crystallography, X-Ray; D006364:Hedgehogs / Q000378:metabolism; D008988:Herpestidae / Q000378:metabolism; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D000073177:Naja haje / Q000502:physiology; D009498:Neurotoxins / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012788:Shrews / Q000378:metabolism; D012909:Snake Bites / Q000378:metabolism / Q000517:prevention & control*; D013816:Thermodynamics
chemical_list: D002038:Bungarotoxins; D009498:Neurotoxins; D011978:Receptors, Nicotinic
keywords: alpha neurotoxin; molecular docking and simulation; nicotinic acetylcholine receptors; snake bite; α-bungarotoxin