Počet záznamů: 1  

Structural Insight into Specificity of Interactions between Nonconventional Three-finger Weak Toxin from Naja kaouthia (WTX) and Muscarinic Acetylcholine Receptors

  1. 1.
    0449347 - FGÚ 2016 RIV US eng J - Článek v odborném periodiku
    Lyukmanova, E. N. - Shenkarev, Z. O. - Shulepko, M. A. - Paramonov, A. S. - Chugunov, A. O. - Janíčková, Helena - Dolejší, Eva - Doležal, Vladimír - Utkin, Y.N. - Tsetlin, V.I. - Arseniev, A. S. - Efremov, R. G. - Dolgikh, D. A. - Kirpichnikov, M. P.
    Structural Insight into Specificity of Interactions between Nonconventional Three-finger Weak Toxin from Naja kaouthia (WTX) and Muscarinic Acetylcholine Receptors.
    Journal of Biological Chemistry. Roč. 290, č. 39 (2015), s. 23616-23630. ISSN 0021-9258. E-ISSN 1083-351X
    Grant CEP: GA ČR(CZ) GA14-05696S
    Institucionální podpora: RVO:67985823
    Klíčová slova: computer modeling * G protein-coupled receptor (GPCR) * site-directed mutagenesis
    Kód oboru RIV: ED - Fyziologie
    Impakt faktor: 4.258, rok: 2015

    Weak toxin from Naja kaouthia (WTX) belongs to the group of nonconventional “three-finger” snake neurotoxins. It irreversibly inhibits nicotinic acetylcholine receptors and allosterically interacts with muscarinic acetylcholine receptors (mAChRs). Using site-directed mutagenesis, NMR spectroscopy, and computer modeling, we investigated the recombinant mutant WTX analogue (rWTX) which, compared with the native toxin, has an additional N-terminal methionine residue. In comparison with the wild-type toxin, rWTX demonstrated an altered pharmacological profile, decreased binding of orthosteric antagonist N-methylscopolamine to human M1- and M2-mAChRs, and increased antagonist binding to M3-mAChR. Positively charged arginine residues located in the flexible loop II were found to be crucial for rWTX interactions with all types of mAChR. Computer modeling suggested that the rWTX loop II protrudes to the M1-mAChR allosteric ligand-binding site blocking the entrance to the orthosteric site. In contrast, toxin interacts with M3-mAChR by loop II without penetration into the allosteric site. Data obtained provide new structural insight into the target-specific allosteric regulation of mAChRs by “three-finger” snake neurotoxins
    Trvalý link: http://hdl.handle.net/11104/0250926

     
     
Počet záznamů: 1  

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