Molecular interactions between mecamylamine enantiomers and the transmembrane domain of the human α4β2 nicotinic receptor.
Molecular interactions between mecamylamine enantiomers and the transmembrane domain of the human α4β2 nicotinic receptor.
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DOI：
10.1021/bi400969x
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发表时间：
2014-02-11
期刊：
影响因子：
2.9
通讯作者：
Arias, Hugo R.
中科院分区：
文献类型：
--
作者：
Bondarenko, Vasyl;Targowska-Duda, Katarzyna M.;Jozwiak, Krzysztof;Tang, Pei;Arias, Hugo R.
为了表征甲美胺对映体在人(h) (α4)3(β2)2和（α4）2(β2)3烟碱受体（AChRs）跨膜结构域（TMD）上的结合位点，我们采用了核磁共振（NMR）、分子对接和放射性配体结合等方法。hα4β2-TMD内(S)-(+)-和(R)-(−)-甲胺与若干残基的相互作用，通过高分辨率核磁共振测定，表明在若干腔内(L)和非腔内（NL）位点上存在不同的结合模式。一般来说，对每个甲胺对映体敏感的残基在两种受体化学计量上是相似的。然而，观察到一些差异。分子对接实验对于描述每个对映体在其结合位点的位置和方向至关重要。在（α4）2(β2)3- tmd中，(S)-(+)-甲胺与L1位点（即−3′和−5′之间）和L2位点（即16′和20′之间）相互作用，而β2-亚基间（即两个β2- tmds的细胞质端）和α4/β2-亚基间（即α4- tm1和β2- tm3的细胞质端）位点由两个对映体共享。在（α4）3(β2)2- tmd中，两种对映体都以不同的方向与L1′（更靠近环2′）和α4-亚基内位点（即α4- tm1和α4- tm2的细胞质端）结合，但只有(R)-(−)-甲胺与L2′（更靠近环20′）和α4- tm3亚基内位点相互作用。我们的发现很重要，因为它们首次提供了甲胺对映体在每个hα4β2化学计量中引起的变构调节的结构理解。这一进展可能有助于开发治疗几种神经系统疾病的新疗法。
To characterize the binding sites of mecamylamine enantiomers on the transmembrane domain (TMD) of human (h) (α4)3(β2)2 and (α4)2(β2)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 hα4β2-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 (α4)2(β2)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 β2-intersubunit (i.e., cytoplasmic end of two β2-TMDs) and α4/β2-intersubunit (i.e., cytoplasmic end of α4-TM1 and β2-TM3) sites are shared by both enantiomers. In the (α4)3(β2)2-TMD, both enantiomers bind with different orientations to the L1′ (closer to ring 2′) and α4-intrasubunit (i.e., at the cytoplasmic ends of α4-TM1 and α4-TM2) sites, but only (R)-(−)-mecamylamine interacts with the L2′ (i.e., closer to ring 20′) and α4-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 hα4β2 stoichiometry. This advancement could be beneficial for the development of novel therapies for the treatment of several neurological disorders.
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