Zhang Z P, Shukri M, Gambone C J, Gabriel J L, Soprano K J, Soprano D R
Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Arch Biochem Biophys. 2000 Aug 15;380(2):339-46. doi: 10.1006/abbi.2000.1932.
The biological actions of retinoic acid (RA) are mediated by retinoic acid receptors (RARalpha, -beta, and -gamma) and retinoid X receptors (RXRalpha, -beta, and -gamma). Although the ligand-binding domains of RARs and RXRs have been suggested to share the same novel folding pattern, the ligand-binding pockets of each of the retinoid receptors must have unique structural features since it has been possible to develop RAR subtype-selective and RXR-selective retinoids. We have previously demonstrated the importance for RA binding and RA-dependent transactivation of Arg(276) in RARalpha and Arg(278) in RARgamma; however, in RARbeta Arg(269) functions in conjunction with Lys(220). Here we have examined the role of the hydroxyl group of RARgamma Ser(289) and its homologous amino acid residues in RARalpha (Ser(287)) and RARbeta (Ser(280)) alone and in conjunction with their respective RARgamma Arg(278) homologs for RA binding and RA-dependent transactivation activity. The hydroxyl group of this Ser in all three RARs was found by itself not to be important for RA binding and RA-dependent transactivation activity. However, in RARalpha and RARgamma this Ser appears to play a small role in conjunction with Arg(276) and Arg(278), respectively, for these activities. Alternatively, strong synergism was observed in RARbeta between Ser(280) and Arg(269) for RA-binding and RA-dependent transactivation activity. This provides further evidence that the mechanism of interaction between the carboxylate group of retinoids and the amino acid residues in the ligand binding pocket of RARbeta is different from that of RARalpha and RARgamma.
维甲酸（RA）的生物学作用是由维甲酸受体（RARα、-β和-γ）以及类视黄醇X受体（RXRα、-β和-γ）介导的。尽管已表明RAR和RXR的配体结合结构域具有相同的新型折叠模式，但由于已开发出RAR亚型选择性和RXR选择性类视黄醇，所以每种类视黄醇受体的配体结合口袋必定具有独特的结构特征。我们之前已经证明了RARα中的Arg（276）和RARγ中的Arg（278）对于RA结合和RA依赖性反式激活的重要性；然而，在RARβ中，Arg（269）与Lys（220）共同发挥作用。在此，我们单独研究了RARγ的Ser（289）及其在RARα（Ser（287））和RARβ（Ser（280））中的同源氨基酸残基，以及它们与各自的RARγ Arg（278）同源物结合时对RA结合和RA依赖性反式激活活性的作用。发现所有三种RAR中该Ser的羟基本身对于RA结合和RA依赖性反式激活活性并不重要。然而，在RARα和RARγ中，该Ser分别与Arg（276）和Arg（278）结合时似乎对这些活性发挥了较小的作用。另外，在RARβ中观察到Ser（280）和Arg（269）之间在RA结合和RA依赖性反式激活活性方面有很强的协同作用。这进一步证明了类视黄醇的羧基与RARβ配体结合口袋中的氨基酸残基之间的相互作用机制不同于RARα和RARγ。
