title: Structural determinants for the interactions between muscarinic toxin 7 and muscarinic acetylcholine receptors.
abstract: Muscarinic acetylcholine receptors (mAChRs) have five subtypes and play crucial roles in various physiological functions and pathophysiological processes. Poor subtype specificity of mAChR modulators has been an obstacle to discover new therapeutic agents. Muscarinic toxin 7 (MT7) is a natural peptide toxin with high selectivity for the M1 receptor. With three to five residues substituted, M3, M4, and M5 receptor mutants could bind to MT7 at nanomolar concentration as the M1 receptor. However, the structural mechanisms explaining MT7-mAChRs binding are still largely unknown. In this study, we constructed 10 complex models of MT7 and each mAChR subtype or its mutant, performed molecular dynamics simulations, and calculated the binding energies to investigate the mechanisms. Our results suggested that the structural determinants for the interactions on mAChRs were composed of some critical residues located separately in the extracellular loops of mAChRs, such as Glu4.56, Leu4.60, Glu/Gln4.63, Tyr4.65, Glu/Asp6.67, and Trp7.35. The subtype specificity of MT7 was attributed to the non-conserved residues at positions 4.56 and 6.67. These structural mechanisms could facilitate the discovery of novel mAChR modulators with high subtype specificity and enhance the understanding of the interactions between ligands and G-protein-coupled receptors.
authors: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Jianrong
authors: J
authors: Xu
authors: Hengyi
authors: H
authors: Zhao
authors: Zhaoxi
authors: Z
authors: Zheng
authors: Yu
authors: Y
authors: Wang
authors: Yinyao
authors: Y
authors: Niu
authors: Hao
authors: H
authors: Wang
authors: Jun
authors: J
authors: Xu
authors: Yang
authors: Y
authors: Lu
authors: Hongzhuan
authors: H
authors: Chen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004546:Elapid Venoms / Q000737:chemistry* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D051381:Rats; D011976:Receptors, Muscarinic / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D004546:Elapid Venoms; D011976:Receptors, Muscarinic; C419876:muscarinic toxin 7
keywords: G-protein-coupled receptors; molecular dynamics simulations; muscarinic acetylcholine receptors; muscarinic toxin 7; structural mechanism; virtual mutation