Paper Report for: Bondarenko_2014_Biochemistry_53_908
Reference
Title: Molecular interactions between mecamylamine enantiomers and the transmembrane domain of the human alpha4beta2 nicotinic receptor Bondarenko V, Targowska-Duda KM, Jozwiak K, Tang P, Arias HR Ref: Biochemistry, 53:908, 2014 : PubMed
To characterize the binding sites of mecamylamine enantiomers on the transmembrane domain (TMD) of human (h) (alpha4)3(beta2)2 and (alpha4)2(beta2)3 nicotinic acetylcholine receptors (AChRs), we used nuclear magnetic resonance (NMR), molecular docking, and radioligand binding approaches. The interactions of (S)-(+)- and (R)-(-)-mecamylamine with several residues, determined by high-resolution NMR, within the halpha4beta2-TMD indicate different modes of binding at several luminal (L) and nonluminal (NL) sites. In general, the residues sensitive to each mecamylamine enantiomer are similar at both receptor stoichiometries. However, some differences were observed. The molecular docking experiments were crucial for delineating the location and orientation of each enantiomer in its binding site. In the (alpha4)2(beta2)3-TMD, (S)-(+)-mecamylamine interacts with the L1 (i.e., between positions -3' and -5') and L2 (i.e., between positions 16' and 20') sites, whereas the beta2-intersubunit (i.e., cytoplasmic end of two beta2-TMDs) and alpha4/beta2-intersubunit (i.e., cytoplasmic end of alpha4-TM1 and beta2-TM3) sites are shared by both enantiomers. In the (alpha4)3(beta2)2-TMD, both enantiomers bind with different orientations to the L1' (closer to ring 2') and alpha4-intrasubunit (i.e., at the cytoplasmic ends of alpha4-TM1 and alpha4-TM2) sites, but only (R)-(-)-mecamylamine interacts with the L2' (i.e., closer to ring 20') and alpha4-TM3-intrasubunit sites. Our findings are important because they provide, for the first time, a structural understanding of the allosteric modulation elicited by mecamylamine enantiomers at each halpha4beta2 stoichiometry. This advancement could be beneficial for the development of novel therapies for the treatment of several neurological disorders.
        
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Bondarenko V, Targowska-Duda KM, Jozwiak K, Tang P, Arias HR (2014) Molecular interactions between mecamylamine enantiomers and the transmembrane domain of the human alpha4beta2 nicotinic receptor Biochemistry53: 908-18