The cyclooxygenase activity of the membrane protein prostaglandin H2 synthase isoform 1 (PGHS-1) is the target of the nonsteroidal antiinflammatory drugs (NSAIDs). The X-ray crystal structures of PGHS-1 in complex with the NSAIDs flurbiprofen and bromoaspirin have been determined previously [Picot, D., et al. (1994) Nature 367, 243-249; Loll, P. J., et al. (1995) Nat. Struct. Biol. 2, 637-643]. We report here the preparation and characterization of novel potent iodinated analogs of the NSAIDs indomethacin and suprofen, as well as the refined X-ray crystal structures of their complexes with PGHS-1. The PGHS-iodosuprofen complex structure has been refined at 3.5 A to an R-value of 0.189 and shows the suprofen analog to share a common mode of binding with flurbiprofen. The PGHS-iodoindomethacin complex structure has been refined at 4.5 A to an R-value of 0.254. The low resolution of the iodoindomethacin complex structure precludes detailed modeling of drug-enzyme interactions, but the electron-dense iodine atom of the inhibitor has been unambiguously located, allowing for the placement and approximate orientation of the inhibitor in the enzyme's active site. We have modeled two equally likely binding modes for iodoindomethacin, corresponding to the two principal conformers of the inhibitor. Like flurbiprofen, iodosuprofen and iodoindomethacin bind at the end of the long channel which leads into the enzyme active site. Binding at this site presumably blocks access of substrate to Tyr-385, a residue essential for catalysis. No evidence is seen for significant protein conformational differences between the iodoindomethacin and iodosuprofen of flurbiprofen complex structures.

中文翻译：

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碘化非甾体类抗炎药类似物的合成和用作前列腺素H2合酶环加氧酶活性位点的晶体学探针。

膜蛋白前列腺素H2合酶同工型1（PGHS-1）的环氧合酶活性是非甾体抗炎药（NSAIDs）的目标。先前已经确定了与NSAIDs氟比洛芬和溴阿司匹林复合的PGHS-1的X射线晶体结构[Picot，D。，等人。（1994）Nature 367，243-249; Loll，PJ等。（1995）Nat。结构。生物学 2，637-643]。我们在这里报告了NSAIDs吲哚美辛和Suprofen的新型有效碘化类似物的制备和表征，以及它们与PGHS-1配合物的精制X射线晶体结构。PGHS-碘普洛芬复合物的结构在3.5 A下已被精修至R值为0.189，显示出Suprofen类似物与氟比洛芬具有共同的结合方式。PGHS-碘吲哚美辛复合物的结构已在4处精制。5 A至R值为0.254。碘吲哚美辛复合物结构的低分辨率无法进行药物-酶相互作用的详细建模，但是抑制剂的电子致密碘原子已明确定位，从而可以将抑制剂放置在酶的活性位点并使其大致定向。我们已经建模了碘吲哚美辛的两种同样可能的结合模式，分别对应于抑制剂的两个主要构象体。像氟比洛芬一样，碘普洛芬和碘吲哚美辛在长通道末端结合，从而进入酶的活性位点。据推测，在该位点的结合会阻止底物接近Tyr-385，而Tyr-385是催化必不可少的残基。没有证据表明氟比洛芬复合物结构的碘吲哚美辛和碘磺洛芬之间存在显着的蛋白质构象差异。