IGBMC, Upr Biologie Structurale (9004) Parc D'Innovation, 1 Rue Laurent Fries, Bp 163 Illkirch Cedex 67404 FRANCE
To activate transcription of target genes, Nuclear Receptors (NRs) require the binding of their cognate ligand to their Ligand Binding Domain (LBD). Recently, the 3D crystallographic structures of the apo hRXRa (1) and the holo hRARg/9cis-RA(2) NRs have been determined. Comparison of the 3D structures of the unliganded and liganded forms have been exploited to derive a general sequence alignment of the LBD of numerous members of the NR superfamily. A 20 amino acid stretch constitutes a NR specific signature which contains most of the conserved residues that stabilize the core of the canonical fold. From the sequence / structure comparison, an alignment of the NR superfamily is proposed(4). The sequence alignment correctly located all the helices for the rat thyroid hormone receptor a1 (rTRa) bound to a thyroid hormone agonist(3), specially helix H1 and H12 at the N-ter and C-ter, respectivelly, of the LBD domain. The alignment highlights also a common ligand binding pocket involving predominantly hydrophobic residues. Most of the key residues delineating the pocket of rTRa. are correctly predicted. Homology modelling of the holo LBDs of the hRXRa/9cis-RA and glucocortico=EFd receptor bound to a synthetic agonist (dexamethasone) reveal the 3D lineup of the residues involved in ligand binding in both complexes(4). Mutant studies support these models, as well as a general mechanism for ligand induced activation deduced from the comparison of the transcriptionally active hRARg holo- and inactive RXRa apo- LBD structures(4).
(1) W. Bourguet, M. Ruff, P. Chambon, H. Gronemeyer and D. Moras, Nature, 375, 377-382, 1995
(2) J. P. Renaud, N. Rochel, M. Ruff, V. Vivat, P. Chambon, H. Gronemeyer and D. Moras, Nature, 378, 681-689, 1995
(3) R. Wagner, J. W. Apriletti, M. E. McGrath, B. L. West, J. D. Baxter and
R. J. Fletterick, Nature, 378, 690-697, 1995
(4) J. M. Wurtz, W. Bourguet, J. P. Renaud, V. Vivat, P. Chambon, D. Moras and H. Gronemeyer,
Nature Structural Biology, 3, 87-94, 1996;
Erratum, Nature Structural Biology, 3, 206, 1996