Structural basis for isotype selectivity of the human retinoic acid nuclear receptor
Structural basis for isotype selectivity of the human retinoic acid nuclear receptor
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DOI：
10.1006/jmbi.2000.4032
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发表时间：
2000-09-08
影响因子：
5.6
通讯作者：
Moras, D
中科院分区：
文献类型：
--
作者：
Klaholz, BP;Mitschler, A;Moras, D
人视黄酸受体（human retinoic acid receptor，hRAR）属于以配体依赖性方式调节转录的核受体家族。同种型RAR α、β和γ是参与治疗各种皮肤疾病和癌症，特别是乳腺癌和急性早幼粒细胞白血病的类维生素A的不同药理学靶标。因此，已经开发了合成类维生素A，旨在同种型选择性和减少副作用。我们报告了与激动剂类维生素A结合的hRAR γ配体结合结构域（LBD）的三种复合物的晶体结构，所述类维生素A具有对RAR γ（BMS 184394）或RAR β/γ（CD 564）的选择性，或者对所有RAR同种型（泛激动剂BMS 181156）有效。高分辨率数据（1.3-1.5埃）提供了在配体袋的原子水平上的描述，揭示了不同程度的配体选择性的分子决定因素。化学上密切相关的类维生素A BMS 184394和CD 564的复合物的比较表明，Met 272的侧链根据其硫原子和配体之间氢键的存在而采用不同的构象。这解释了它们不同的同种型选择性。另一方面，泛-和RAR β，γ-选择性激动剂之间的差异可能是由于在CD 564的2-萘甲酸部分的水平上的空间分辨。基于这项研究，我们提出了一个模型的RAR γ-特异性激动剂CD 666，显示了RAR同种型选择性类维生素A的基于结构的药物设计的可能应用程序的复合物。(C)北京大学出版社.
The human retinoic acid receptor (hRAR) belongs to the family of nuclear receptors that regulate transcription in a ligand-dependent way. The isotypes RAR alpha,beta and gamma are distinct pharmacological targets for retinoids that are involved in the treatment of various skin diseases and cancers, in particular breast cancer and acute promyelocytic leukemia. Therefore, synthetic retinoids have been developed aiming at isotype selectivity and reduced side-effects. We report the crystal structures of three complexes of the hRAR gamma ligand-binding domain (LBD) bound to agonist retinoids that possess selectivity either for RAR gamma (BMS184394) or for RAR beta/gamma (CD564), or that are potent for all RAR-isotypes (panagonist BMS181156). The high resolution data (1.3-1.5 Angstrom) provide a description at the atomic level of the ligand pocket revealing the molecular determinants for the different degrees of ligand selectivity. The comparison of the complexes of the chemically closely related retinoids BMS184394 and CD564 shows that the side-chain of Met272 adopts different conformations depending on the presence of a hydrogen bond between its sulfur atom and the ligand. This accounts for their different isotype selectivity. On the other hand, the difference between the pan- and the RAR beta,gamma-selective agonist is probably due to a steric discrimination at the level of the 2-naphthoic acid moiety of CD564. Based on this study, we propose a model for a complex with the RAR gamma-specific agonist CD666 that shows the possible applications for structure-based drug design of RAR isotype-selective retinoids. (C) 2000 Academic Press.