X-ray crystallographic identification of a protein-binding site for both all-trans- and 9-cis-retinoic acid.
X-ray crystallographic identification of a protein-binding site for both all-trans- and 9-cis-retinoic acid.
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全反式和 9-顺式视黄酸的蛋白质结合位点的 X 射线晶体学鉴定。
DOI：
10.1073/pnas.90.19.9223
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发表时间：
1993
影响因子：
11.1
通讯作者：
Ong,DE
中科院分区：
文献类型：
--
作者：
Newcomer,ME;Pappas,RS;Ong,DE
由于最近发现了视黄酸核受体的结合特异性，阐明蛋白质结合位点如何特异性识别视黄酸的全反式和9顺式异构体是特别有趣的。已经描述了两个维甲酸核受体家族，分别命名为RAR（维甲酸受体）和RXR（维甲酸- x受体）。RXR受体家族对9-顺式维甲酸具有特异性，而rar型受体可被9-顺式或全反式维甲酸激活。在对分泌的附睾维甲酸结合蛋白（含或不含维甲酸）的x射线结构测定中，我们观察到结合的全反式维甲酸的电子密度，表明蛋白质结合的维生素/激素的全反式采用类似于配体9-顺式异构体的结构的马蹄形构象。我们在这里详细的实验表明，电子密度确实是由于全反式维甲酸和蛋白质也可以结合9-顺式异构体。这一观察结果和相同的蛋白质也结合合成维甲酸(E)-4-[2-（5,6,7,8-四氢-5,5,8,8-四甲基-2-萘基）-1-丙烯]-苯甲酸（TTNPB），一种激活RAR但不激活RXR的维甲酸类似物，表明该蛋白质识别9-顺式和全反式维甲酸的机制可能与RAR使用的机制相似。已经描述了视黄醇结合蛋白的三种晶体结构。在这些结构中，视黄醇与完全伸展的异戊二烯尾部结合。该报告代表了采用非延伸构象的蛋白质结合类维甲酸构象的x射线晶体学描述，我们相信这一观察结果与维甲酸受体描述的配体特异性有关。
The elucidation of how a protein-binding site might specifically recognize both the all-trans and 9-cis isomers of retinoic acid is of particular interest because of the recently discovered binding specificities of the nuclear receptors for retinoic acid. Two families of nuclear receptors for retinoic acid have been described, which are designated RAR (for retinoic acid receptor) and RXR (for retinoid-X receptor). The RXR family of receptors is specific for 9-cis-retinoic acid, whereas the RAR-type receptor is activated by either 9-cis- or all-trans-retinoic acid. During the x-ray structure determination of a secreted epididymal retinoic acid-binding protein, with and without retinoic acid, we observed an electron density for the bound all-trans-retinoic acid that indicates the protein-bound all-trans form of the vitamin/hormone adopts a horseshoe-like conformation that resembles the structure of the 9-cis isomer of the ligand. We detail here the experiments that indicate the electron density is indeed due to all-trans-retinoic acid and that protein can also bind the 9-cis isomer. This observation and the fact that the same protein also binds the synthetic retinoid (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1- propenyl]-benzoic acid (TTNPB), a retinoic acid analog that activates RAR but does not activate RXR, suggest that the mechanism by which this protein recognizes both 9-cis- and all-trans-retinoic acids may be analogous to the mechanism used by RAR. Three crystallographic structures of retinol-binding proteins have been described. In each of these structures the retinol binds with the isoprene tail fully extended. This report represents an x-ray crystallographic description of a protein-bound retinoid conformer that adopts a nonextended conformation, and we believe this observation is relevant to the ligand specificities described for the retinoic acid receptors.