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首页> 外文期刊>Biochemistry >Structures of Cytochrorne P450 2B4 Complexed with the Antiplatelet Drugs Ticlopidine and Clopidogrel
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Structures of Cytochrorne P450 2B4 Complexed with the Antiplatelet Drugs Ticlopidine and Clopidogrel

机译：Cytochrorne P450 2B4与抗血小板药物噻氯匹定和氯吡格雷复合的结构

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Prior X-ray crystal structures of rabbit cytochrome P450 2B4 (2B4) in complexes with various imidazoles have demonstrated markedly different enzyme conformations depending on the size of the inhibitor occupying the active site. In this study, structures of 2B4 were determined with the antiplatelet drugs clopidogrel and ticlopidine, which were expected to have greater freedom of movement in the binding pocket.Ticlopidine could be modeled into the electron density maps in two distinct orientations, both of which are consistent with metabolic data gathered with other mammalian P450 enzymes. Results of ligand docking and heme-induced NM R relaxation of drug protons showed that ticlopidine was preferentially oriented with the chlorophenyl group closest to the heme. Because of its stereocenter, clopidogrel was easier to fit in the electron density and exhibited a single orientation, which points the chlorophenyl ring toward the heme. The C_α traces of both complexes aligned very well with each other and revealed a compact, closed structure that resembles the conformation observed in two previously determined 2B4 structures with the small molecule inhibitors 4-(4- chlorophenyl)imidazole and l-(4-chlorophenyl)imidazole. The 2B4 active site is able to accommodate small ligands by moving only a small number of side chains, suggesting that ligand reorientation is energetically favored over protein conformational changes for binding of these similarly sized molecules.Adjusting both protein conformation and ligand orientation in the active site gives 2B4 the flexibility to bind to the widest range of molecules, while also being energetically favorable.
机译：与各种咪唑配合的兔细胞色素P450 2B4（2B4）的先前X射线晶体结构已显示出显着不同的酶构象，具体取决于占据活性位点的抑制剂的大小。在这项研究中，使用抗血小板药物氯吡格雷和噻氯匹定确定了2B4的结构，它们有望在结合口袋中具有更大的运动自由度。噻氯匹定可以在两个不同的方向上建模成电子密度图，两者是一致的与其他哺乳动物P450酶收集的代谢数据。配体对接和血红素引起的药物质子的NM R弛豫的结果表明，噻氯匹定优先定位于最靠近血红素的氯苯基上。由于其立体中心，氯吡格雷更容易适应电子密度并显示出单一方向，该方向使氯苯环指向血红素。两种配合物的C_α痕迹彼此排列得很好，并显示出紧密的封闭结构，类似于在先前确定的两个2B4结构中观察到的小分子抑制剂4-（4-氯苯基）咪唑和1-（4-氯苯基）构象。咪唑2B4活性位点仅通过移动少量侧链就能容纳小的配体，这表明与这些构象大小相似的分子结合时，与蛋白质构象变化相比，配体的重新定向在能量上更受青睐。使2B4具有与最广泛分子结合的灵活性，同时在能量上也很有利。

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