Binding of the respiratory chain inhibitor antimycin to the mitochondrial bc1 complex:: A new crystal structure reveals an altered intramolecular hydrogen-bonding pattern
Binding of the respiratory chain inhibitor antimycin to the mitochondrial bc1 complex:: A new crystal structure reveals an altered intramolecular hydrogen-bonding pattern
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DOI：
10.1016/j.jmb.2005.05.053
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发表时间：
2005-08-19
影响因子：
5.6
通讯作者：
Berry, EA
中科院分区：
文献类型：
--
作者：
Huang, LS;Cobessi, D;Berry, EA
抗霉素A（antimycin）是最早发现的最有效的线粒体呼吸链抑制剂之一，它与细胞色素bc（1）复合物的醌还原位点结合。结构-活性关系研究表明，N-甲酰氨基水杨酰胺基团是主要的结合特异性基团，酚羟基的低pK（a）和羟基与水杨酰胺键的羰基之间的分子内氢键是重要的。本文报道了牛线粒体bc（1）复合物的一种新结构，其分辨率为2.28 A，与抗霉素结合，这使我们首次可靠地描述了抗霉素的结合，并表明在溶液和小分子结构中描述的分子内氢键被涉及酰胺键的NH而不是羰基O的氢键所取代，酰胺基相对于芳环旋转。酚羟基和甲酰氨基N与细胞色素B的保守Asp 228形成氢键，甲酰氨基OH通过水分子与Lys 227形成氢键。在双内酯环的另一侧和α A螺旋之间发现了双原子分子的高密度、正确的大小和形状。(c)2005爱思唯尔有限公司保留所有权利。
Antimycin A (antimycin), one of the first known and most potent inhibitors of the mitochondrial respiratory chain, binds to the quinone reduction site of the cytochrome bc(1) complex. Structure-activity relationship studies have shown that the N-formylamino-salicyl-amide group is responsible for most of the binding specificity, and suggested that a low pK(a) for the phenolic OH group and an intramolecular H-bond between that OH and the carbonyl 0 of the salicylamide linkage are important.Two previous X-ray structures of antimycin bound to vertebrate bc(1) complex gave conflicting results. A new structure reported here of the bovine mitochondrial bc(1) complex at 2.28 A resolution with antimycin bound, allows us for the first time to reliably describe the binding of antimycin and shows that the intramolecular hydrogen bond described in solution and in the small-molecule structure is replaced by one involving the NH rather than carbonyl O of the amide linkage, with rotation of the amide group relative to the aromatic ring. The phenolic OH and formylamino N form H-bonds with conserved Asp228 of cytochrome b, and the formylamino OH-bonds via a water molecule to Lys227. A strong density, the right size and shape for a diatomic molecule is found between the other side of the dilactone ring and the alpha A helix. (c) 2005 Elsevier Ltd. All rights reserved.