Jacoby E M, Schlichting I, Lantwin C B, Kabsch W, Krauth-Siegel R L
Institut für Biochemie II, Universität Heidelberg, Germany.
Proteins. 1996 Jan;24(1):73-80. doi: 10.1002/(SICI)1097-0134(199601)24:1<73::AID-PROT5>3.0.CO;2-P.
The three-dimensional structure of the complex between Trypanosoma cruzi trypanothione reductase (TR) (EC 1.6.4.8) and the antiparasitic drug mepacrine (quinacrine) has been solved at 2.9 angstoms resolution. Mepacrine is a competitive inhibitor of TR but does not affect human glutathione reductase (GR), a closely related host enzyme. Of particular importance for inhibitor binding are four amino acid residues in the disulfide substrate-binding site of TR that are not conserved in human GR, namely, Glu-18 (Ala-34 in GR), Trp-21 (Arg-37), Ser-109 (Ile-113), and Met-113 (Asn-117). The acridine ring of mepacrine is fixed at the active site close to the hydrophobic wall formed by Trp-21 and Met-113. Specific pairwise interactions between functional groups of the drug and amino acid side chains include the ring nitrogen and Met-113, the chlorine atom and Trp-21, and the oxymethyl group and Ser-109. The alkylamino chain of mepacrine points into the inner region of the active site and is held in position by a solvent-mediated hydrogen bond to Glu-18. The structure of the complex shows for the first time the atomic interactions between TR and an inhibitory ligand. This is a crucial step towards the rational design of inhibitors that might be suited as drugs against Chagas' disease.
克氏锥虫的锥虫硫醇还原酶（TR）（EC 1.6.4.8）与抗寄生虫药物米帕林（奎纳克林）复合物的三维结构已在2.9埃分辨率下解析出来。米帕林是TR的竞争性抑制剂，但不影响人类谷胱甘肽还原酶（GR），后者是一种密切相关的宿主酶。对于抑制剂结合特别重要的是TR的二硫键底物结合位点中的四个氨基酸残基，它们在人类GR中并不保守，即Glu-18（GR中的Ala-34）、Trp-21（Arg-37）、Ser-109（Ile-113）和Met-113（Asn-117）。米帕林的吖啶环固定在靠近由Trp-21和Met-113形成的疏水壁的活性位点处。药物官能团与氨基酸侧链之间的特定成对相互作用包括环氮与Met-113、氯原子与Trp-21以及羟甲基与Ser-109。米帕林的烷基氨基链指向活性位点的内部区域，并通过与Glu-18的溶剂介导氢键保持在该位置。该复合物的结构首次展示了TR与抑制性配体之间的原子相互作用。这是朝着合理设计可能用作治疗恰加斯病药物的抑制剂迈出的关键一步。
