0165-6147/00/$ – see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S0165-6147(99)01443-1 TiPS – March 2000 (Vol. 21) 87 unknown subtype of the TLX receptor, PNR (photoreceptor cell-specific nuclear receptor), was discovered in humans and shown to be expressed only in the retina 12 , confirming this assumption. Concluding remarks Thus, it is an exciting possibility that many novel nuclear recep- tors will also be identified in the human and possibly will represent homologues to those identified in C. elegans. Sev- eral of these receptors have been implicated in functions in C. elegans such as odorant response, sex determination, em- bryonic development and metabolic control. Identification of mammalian homologues will undoubtedly provide important new insights into these areas. Note added in proof On 31 December 1999, the complete sequence of the D. melanogaster genome became available. Notably, this organism appears to possess only few nuclear receptors in addition to those previously known, which might indicate that the multitude of receptors found in C. elegans is unique to this organism. However, proving or disproving this theory must await the characterization of more genomes, the most interesting in this respect being a mammalian genome (e.g. the human genome). Selected references 1 Gronemeyer, H. and Laudet, V. (1995) Transcription factors 3: nuclear receptors. Protein Profile 2, 1173–1308 2 Enmark, E. and Gustafsson, J-Å. (1996) Orphan nuclear receptors – the first eight years. Mol. Endocrinol. 10, 1293–1307 3 C. elegans Sequencing Consortium (1998) Genome sequence of the nema- tode C. elegans: a platform for investigating biology. Science 282, 2012–2018 4 Chervitz, S.A. et al. (1998) Comparison of the complete protein sets of worm and yeast: orthology and divergence. Science 282, 2022–2028 5 Sluder, A.E. et al. (1999) The nuclear receptor superfamily has undergone extensive proliferation and diversification in nematodes. Genome Res. 9, 103–120 6 Laudet, V. (1997) Evolution of the nuclear receptor superfamily: early diversification from an ancestral orphan receptor. J. Mol. Endocrinol. 19, 207–226 7 Zilliacus, J. et al. (1995) Structural determinants of DNA-binding specificity by steroid receptors. Mol. Endocrinol. 9, 389–400 8 Escriva, H. et al. (1997) Ligand binding was acquired during evolution of nuclear receptors. Proc. Natl. Acad. Sci. U. S. A. 94, 6803–6808 9 Yamamoto, K.R. (1997) Intracellular receptors: new instruments for a symphony of signals. In Molecular Biology of Steroid and Nuclear Hormone Receptors (Freedman, L.P., ed.), pp. vii–x, Birkhauser 10 Sengupta, P. et al. (1994) The C. elegans gene odr-7 encodes an olfactory- specific member of the nuclear receptor superfamily. Cell 79, 971–980 11 Sluder, A.E. et al. (1997) The Caenorhabditis elegans orphan nuclear hormone receptor gene nhr-2 functions in early embryonic development. Dev. Biol. 184, 303–319 12 Kobayashi, M. et al. (1999) Identification of a photoreceptor cell-specific nuclear receptor. Proc. Natl. Acad. Sci. U. S. A. 96, 4814–4819 Acknowledgements This work was supported by grants from the Swedish Medical Research Council (No. 13X-2819) and from KaroBio AB. VIEWPOINT PRINCIPLES On the strength of only subtle similarities in primary structures, numerous studies have addressed the question of whether the specific residues of ionotropic glutamate receptors that align with the substrate-binding residues of various periplasmic sub- strate-binding proteins (PBPs), as identified by high-resolution X-ray diffraction, are involved in the recognition of glutamate receptor ligands. Sets of amino acid residues that are probably located in the ligand-binding pocket of ionotropic glutamate receptors were identified by monitoring the effects of mu- tations of these residues on: (1) agonist-elicited channel acti- vation and desensitization; (2) inhibition of channel activity by various competitive receptor antagonists; or (3) the binding of various glutamate receptor ligands (reviewed in Refs 1, 2). Furthermore, theoretical three dimensional (3D) models of these domains have been constructed by computer-assisted molecular modelling using the X-ray coordinates of various PBPs as templates despite the overall low sequence similarity between ionotropic glutamate receptors and PBPs (~12%) 3–10 . These 3D models correspond either to the entire ligand- binding domain (~250 extracellular amino acids) or are limited to the ligand-binding pocket 6 . Recently, Gouaux and co-workers obtained large amounts of a water-soluble, functional, monomeric ligand-binding domain (S1S2 fragment) of an AMPA-preferring receptor sub- unit (GluR2 of rat) 11 and subsequently solved its 3D structure by X-ray crystallographic studies 12 . The crystal structure of the How well can molecular modelling predict the crystal structure: the case of the ligand-binding domain of glutamate receptors Yoav Paas, Anne Devillers-Thiéry, Vivian I. Teichberg, Jean-Pierre Changeux and Miriam Eisenstein The concept that the ligand-binding domain of vertebrate glutamate receptor channels and bacterial periplasmic substrate-binding proteins (PBPs) share similar three-dimensional (3D) structures has gained increasing support in recent years. On the basis of a dual approach that included computer-assisted molecular modelling and functional studies of site-specific mutants, theoretical 3D models of this domain have been proposed. This article reviews to what extent these models could predict the crystal structure of the ligand-binding domain of an ionotropic glutamate receptor subunit recently determined at high resolution by X-ray diffraction studies. Y. Paas, Postdoctoral fellow, E-mail: ypaas@ pasteur.fr A. Devillers- Thiéry, Professor, E-mail: devill@ pasteur.fr J-P. Changeux, Professor, Unité de Neurobiologie Moléculaire, CNRS UA D1284, Institut Pasteur, 25 Rue du Dr Roux, 75015 Paris, France. E-mail: changeux@ pasteur.fr V.I. Teichberg, Professor, Department of Neurobiology, E-mail: vivian.teichberg @weizmann.ac.il and M. Eisenstein, Senior staff scientist, Department of Chemical Services, The Weizmann Institute of Science, 76100 Rehovot, Israel. E-mail: miriam. eisenstein@ weizmann.ac.il