Retinoic acid receptor ligand binding domain

Tian, K., Norris, A.W., Lin, C.L. and Li, E. (1997) The isolation and characterization of purified heterocomplexes of recombinant retinoic acid receptor and retinoid X receptor ligand binding domains. Biochemistry, 36, 5669-5676. 

In another recent example, Hashimoto reported photoaffinity experiments on retinoic acid receptors (RAR). Retinoic acid plays a critical role in cell proliferation and differentiation. RARs belong to the superfamily of nuclear/ thyroid hormone receptors. They consist of six transmembrane domains (A-F) which is a general feature of these receptors. The A/B domains have an autonomous transactivation function while the C-domain contains the Zn-finger, which binds to DNA. The large E-domain participates in ligand binding, dimerization, and ligand dependent transactivation. Finally, D- and F-domains help the orientation and stabilization of the E-domain. 

Fig. 8.2 The ligand-binding domain of the nuclear receptor RXR binds the small molecule 9-cis retinoic acid 9-cis RA). In the apo-structure on the left, helix 12 (H12) extends out into the solution. Upon binding 9-cis RA, HI2 folds back on top of the ligand and LBD creating a binding site for the transcription machinery. The transcription machinery is thereby recruited to the transcription start site, resulting in activation of transcription. Nuclear receptors generally follo A/ this mechanism of ligand-activated transcription. Coordinates from ILBD [9] and 1 FBY [10].

Fig. 11.11 Structure of a fraction (residues 178-423) of the ligand-binding domain of the human retinoic acid receptor, RARy bound to aittians retinoic acid. The Igand, alttrans retinoic acid, is shown as a sdck-and-ball structure. The structure is typical of the ligandbinding domains of nuclear receptors in general. The 2.0 A crystal structure reveals the ligandbinding interactions. The overall fold of the binding pocket is similar to that of the human RXRa LBD. The ligandbinding pockets of the o,p,y- isoforms of RARs differ only in three residues. These three residues seem to be responsible for the differences between the three RAR subtypes. (Reproduced with permission of Professor D. Moras and Nature from the data in Fig. 1 of ref. 38. and the corresponding data available in protein databanks. See also ref. 39.)...

Figure 2 Nuclear hormone receptor structure and ligands, (a) The functional domains of nuclear hormone receptors. They act as either homodimers or heterodimers with a ligand binding domain and a DNA binding domain that are separated by a linker sequence, (b) The conformational change in helix 12 when ligand binding occurs (61, 62). All-trans retinoic acid is shown behind helix 12. (c) Examples of synthetic ligands for estrogen receptor (SERMs) and thyroid hormone receptor (Thyromimetics).

The understanding of the mechanism by which retinoids modulate gene expression implies that retinoids activate a signal-transduction pathway in which nuclear-retinoid receptors, which are members of the steroid hormone-receptor superfamily, play a pivotal role (14,16,18-22). Like other members of this family, the retinoid receptors are ligand-activated, DNA-binding transacting, transcription-modulating proteins. Two types of receptor have been identified retinoic acid receptors (RARs) and retinoid X receptors (RXRs) each type includes three subtypes of RAR (a, p, and y) and of RXR (a, P, and y) with distinct ammo- and carboxy-terminal domains. RXR-RAR... 

Sasaki, T., Shimazawa, R., Sawada, T, Iijima, T, Fukasawa, H, Shudo, K, Hashimoto, Y., and Iwasaki, S (1995) Determination of the photoaffmity-labeled site on the ligand-binding domain of retinoic acid receptor a Biochem Biophys Res. Comm. 207, 444-451... 

Renaud J-P, Rochel N, Ruff M, Vivat V, Chambon P, Gronemeyer H, Moras D (1995) Crystal structure of the RAR-y ligand-binding domain bound to aA-trans retinoic acid. Nature 378 681-689 O Malley BW, Conneely OM (1992) Orphan receptors in search of a unifying hypothesis for activation. Mol Endocrinol 6 1359-1361... 

Lamour FPY, Lardelli P, Apfel CM (1996) Analysis of the ligand-binding domain of human retinoic acid receptor a by site-directed mutagenesis. Mol Cell Biol 16 5386-5392... 

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