Structural studies on nuclear receptors

Abstract. Nuclear receptors are DNA-binding factors which regulate the transcription of sets of specific genes in response to cognate ligands, usually small lipophilic molecules, thus controlling numerous physiological events in development, procreation, homeostasis, and cellular life. Their ligand-dependent activity makes nuclear receptors obvious targets for drug design in many therapeutic areas. Crystallographic studies have revealed the structure of isolated domains but not, yet, of a whole protein, probably due to an intrinsic flexibility at work in nuclear receptor action. The structure of DNA-binding domain dimers in complex with an oligonucleotide has brought insights into how nuclear receptors recognize and bind to their target sequences (‘response elements’). The structure of several ligand-binding domains in different ligation states has provided evidence for a ligand-dependent transcriptional switch and a molecular basis for the mode of action of agonists and antagonists.

[1]  H. Samuels,et al.  Interactions among a subfamily of nuclear hormone receptors: the regulatory zipper model. , 1990, Molecular endocrinology.

[2]  M. Privalsky,et al.  A Conformational Switch in Nuclear Hormone Receptors Is Involved in Coupling Hormone Binding to Corepressor Release , 1998, Molecular and Cellular Biology.

[3]  C. D. Jones,et al.  Molecular determinants of tissue selectivity in estrogen receptor modulators. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[4]  C. Glass,et al.  Nuclear receptor coactivators. , 1997, Current opinion in cell biology.

[5]  K. Yamamoto,et al.  The function and structure of the metal coordination sites within the glucocorticoid receptor DNA binding domain , 1988, Nature.

[6]  M Carlquist,et al.  Structure of the ligand‐binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist , 1999, The EMBO journal.

[7]  K. Yamamoto,et al.  Solution structure of the glucocorticoid receptor DNA-binding domain. , 1990, Science.

[8]  V. Laudet,et al.  Evolution of the nuclear receptor superfamily: early diversification from an ancestral orphan receptor. , 1997, Journal of molecular endocrinology.

[9]  M. Lazar,et al.  The CoRNR motif controls the recruitment of corepressors by nuclear hormone receptors , 1999, Nature.

[10]  D. Moras,et al.  Characterization of the DNA-Binding and Dimerization Properties of the Nuclear Orphan Receptor Germ Cell Nuclear Factor , 1999, Molecular and Cellular Biology.

[11]  P B Sigler,et al.  Crystallographic comparison of the estrogen and progesterone receptor's ligand binding domains. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[12]  P. Sigler,et al.  The basis for half-site specificity explored through a non-cognate steroid receptor-DNA complex , 1995, Nature Structural Biology.

[13]  M Karplus,et al.  Retinoic acid receptor: a simulation analysis of retinoic acid binding and the resulting conformational changes. , 1999, Journal of molecular biology.

[14]  M. Parker,et al.  Molecular Determinants of the Estrogen Receptor-Coactivator Interface , 1999, Molecular and Cellular Biology.

[15]  B. Luisi,et al.  A recipe for specificity , 1995, Nature Structural Biology.

[16]  H. Dyson,et al.  DNA-induced conformational changes are the basis for cooperative dimerization by the DNA binding domain of the retinoid X receptor. , 1998, Journal of molecular biology.

[17]  P. Chambon,et al.  Conformational adaptation of agonists to the human nuclear receptor RARγ , 1998, Nature Structural Biology.

[18]  D. Moras,et al.  Structural basis for isotype selectivity of the human retinoic acid nuclear receptor. , 2000, Journal of molecular biology.

[19]  P. Chambon,et al.  Activation function 2 (AF‐2) of retinoic acid receptor and 9‐cis retinoic acid receptor: presence of a conserved autonomous constitutive activating domain and influence of the nature of the response element on AF‐2 activity. , 1994, The EMBO journal.

[20]  H. Gronemeyer,et al.  The coactivator TIF2 contains three nuclear receptor‐binding motifs and mediates transactivation through CBP binding‐dependent and ‐independent pathways , 1998, The EMBO journal.

[21]  C. Glass,et al.  The coregulator exchange in transcriptional functions of nuclear receptors. , 2000, Genes & development.

[22]  P. Chambon,et al.  Promoter context- and response element-dependent specificity of the transcriptional activation and modulating functions of retinoic acid receptors , 1992, Cell.

[23]  N Heinrich,et al.  Three-dimensional models of estrogen receptor ligand binding domain complexes, based on related crystal structures and mutational and structure-activity relationship data. , 1998, Journal of medicinal chemistry.

[24]  R. Roeder,et al.  Ligand induction of a transcriptionally active thyroid hormone receptor coactivator complex. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[25]  H. Dyson,et al.  High-resolution solution structure of the retinoid X receptor DNA-binding domain. , 1998, Journal of molecular biology.

[26]  R Abagyan,et al.  Rational discovery of novel nuclear hormone receptor antagonists , 2000, Proc. Natl. Acad. Sci. USA.

[27]  P. Chambon,et al.  Steroid hormone receptors compete for factors that mediate their enhancer function , 1989, Cell.

[28]  P. Chambon,et al.  Crystal structure of a heterodimeric complex of RAR and RXR ligand-binding domains. , 2000, Molecular cell.

[29]  P Chambon,et al.  Structural basis for engineering of retinoic acid receptor isotype-selective agonists and antagonists. , 1999, Chemistry & biology.

[30]  P. Sigler,et al.  Structural determinants of nuclear receptor assembly on DNA direct repeats , 1995, Nature.

[31]  W. Wahli,et al.  Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay. , 1997, Molecular endocrinology.

[32]  B. Raaka,et al.  The conserved ninth C-terminal heptad in thyroid hormone and retinoic acid receptors mediates diverse responses by affecting heterodimer but not homodimer formation , 1993, Molecular and cellular biology.

[33]  Barry M. Forman,et al.  Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors α and δ , 1997 .

[34]  T. Willson,et al.  The PPARs: From Orphan Receptors to Drug Discovery , 2000 .

[35]  J. Schwabe,et al.  The role of water in protein-DNA interactions. , 1997, Current opinion in structural biology.

[36]  C. Glass.  Differential recognition of target genes by nuclear receptor monomers, dimers, and heterodimers. , 1994, Endocrine reviews.

[37]  D. Moras,et al.  Antagonism in the human mineralocorticoid receptor , 1998, The EMBO journal.

[38]  D. Moore,et al.  Two receptor interacting domains in the nuclear hormone receptor corepressor RIP13/N-CoR. , 1996, Molecular endocrinology.

[39]  D Neuhaus,et al.  DNA recognition by the oestrogen receptor: from solution to the crystal. , 1993, Structure.

[40]  P. Sigler,et al.  Atomic structure of progesterone complexed with its receptor , 1998, Nature.

[41]  P. Chambon,et al.  The dimerization interfaces formed between the DNA binding domains of RXR, RAR and TR determine the binding specificity and polarity of the full‐length receptors to direct repeats. , 1994, The EMBO journal.

[42]  J. Milbrandt,et al.  Participation of non-zinc finger residues in DNA binding by two nuclear orphan receptors. , 1992, Science.

[43]  M. Leid.  Ligand-induced alteration of the protease sensitivity of retinoid X receptor alpha. , 1994, The Journal of biological chemistry.

[44]  S. Kliewer,et al.  Structure of the retinoid X receptor alpha DNA binding domain: a helix required for homodimeric DNA binding. , 1993, Science.

[45]  Zbigniew Dauter,et al.  Molecular basis of agonism and antagonism in the oestrogen receptor , 1997, Nature.

[46]  J. Lehmann,et al.  Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[47]  David M. Heery,et al.  A signature motif in transcriptional co-activators mediates binding to nuclear receptors , 1997, Nature.

[48]  R J Fletterick,et al.  Nuclear-receptor ligands and ligand-binding domains. , 1999, Annual review of biochemistry.

[49]  C. Hänni,et al.  Ligand binding was acquired during evolution of nuclear receptors. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[50]  R. Evans,et al.  The RXR heterodimers and orphan receptors , 1995, Cell.

[51]  Mary E. McGrath,et al.  A structural role for hormone in the thyroid hormone receptor , 1995, Nature.

[52]  P. Chambon,et al.  The N-terminal region of the chicken progesterone receptor specifies target gene activation , 1988, Nature.

[53]  A. Wolffe,et al.  Determinants of chromatin disruption and transcriptional regulation instigated by the thyroid hormone receptor: hormone‐regulated chromatin disruption is not sufficient for transcriptional activation , 1997, The EMBO journal.

[54]  William Bourguet,et al.  Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-α , 1995, Nature.

[55]  P. Chambon,et al.  A mutation mimicking ligand‐induced conformational change yields a constitutive RXR that senses allosteric effects in heterodimers , 1997, The EMBO journal.

[56]  Paul Tempst,et al.  Ligand-dependent transcription activation by nuclear receptors requires the DRIP complex , 1999, Nature.

[57]  F. Jeanmougin,et al.  A possible involvement of TIF1 alpha and TIF1 beta in the epigenetic control of transcription by nuclear receptors. , 1996, The EMBO journal.

[58]  C. Glass,et al.  A nuclear hormone receptor corepressor mediates transcriptional silencing by receptors with distinct repression domains , 1996, Molecular and cellular biology.

[59]  Jasmine Chen,et al.  Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[60]  D. Moras,et al.  The crystal structure of the nuclear receptor for vitamin D bound to its natural ligand. , 2000, Molecular cell.

[61]  J. Lees,et al.  Identification of a conserved region required for hormone dependent transcriptional activation by steroid hormone receptors. , 1992, The EMBO journal.

[62]  M. Tetel.  Nuclear Receptor Coactivators in Neuroendocrine Function , 2000, Journal of neuroendocrinology.

[63]  K. Umesono,et al.  Determinants of target gene specificity for steroid/thyroid hormone receptors , 1989, Cell.

[64]  D. Mangelsdorf,et al.  Nuclear Orphan Receptors: The Search for Novel Ligands and Signaling Pathways , 1998 .

[65]  T. Willson,et al.  Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ , 1998, Nature.

[66]  John W. R. Schwabe,et al.  The crystal structure of the estrogen receptor DNA-binding domain bound to DNA: How receptors discriminate between their response elements , 1993, Cell.

[67]  P. Chambon.  A decade of molecular biology of retinoic acid receptors , 1996, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[68]  A transcriptional silencing domain in DAX-1 whose mutation causes adrenal hypoplasia congenita. , 1997, Molecular endocrinology.

[69]  J. Leers,et al.  Mechanistic Principles in NR Box-Dependent Interaction between Nuclear Hormone Receptors and the Coactivator TIF2 , 1998, Molecular and Cellular Biology.

[70]  P. Lemotte,et al.  Different agonist- and antagonist-induced conformational changes in retinoic acid receptors analyzed by protease mapping , 1994, Molecular and Cellular Biology.

[71]  E. Kalkhoven,et al.  Isoforms of steroid receptor co‐activator 1 differ in their ability to potentiate transcription by the oestrogen receptor , 1998, The EMBO journal.

[72]  J. Schwabe,et al.  The oestrogen receptor recognizes an imperfectly palindromic response element through an alternative side-chain conformation. , 1995, Structure.

[73]  P. Chambon,et al.  TIF2, a 160 kDa transcriptional mediator for the ligand‐dependent activation function AF‐2 of nuclear receptors. , 1996, The EMBO journal.

[74]  Jean-Paul Renaud,et al.  Crystal structure of the RAR-γ ligand-binding domain bound to all-trans retinoic acid , 1995, Nature.

[75]  H. Gronemeyer,et al.  The nuclear receptor ligand-binding domain: structure and function. , 1998, Current opinion in cell biology.

[76]  H. Samuels,et al.  Conformational changes in chicken thyroid hormone receptor alpha 1 induced by binding to ligand or to DNA. , 1993, Biochemistry.

[77]  R. Evans,et al.  Regulation of Hormone-Induced Histone Hyperacetylation and Gene Activation via Acetylation of an Acetylase , 1999, Cell.

[78]  S. Fawell,et al.  Characterization and colocalization of steroid binding and dimerization activities in the mouse estrogen receptor , 1990, Cell.

[79]  S. Schreiber,et al.  Nuclear Receptor Repression Mediated by a Complex Containing SMRT, mSin3A, and Histone Deacetylase , 1997, Cell.

[80]  C. Glass,et al.  Molecular determinants of nuclear receptor-corepressor interaction. , 1999, Genes & development.

[81]  Thorsten Heinzel,et al.  Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor , 1995, Nature.

[82]  J. Gustafsson,et al.  Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists. , 1998, Molecular pharmacology.

[83]  D. Ray,et al.  Structure/function of the human glucocorticoid receptor: tyrosine 735 is important for transactivation. , 1999, Molecular endocrinology.

[84]  M. Karin,et al.  A conserved C-terminal sequence that is deleted in v-ErbA is essential for the biological activities of c-ErbA (the thyroid hormone receptor) , 1993, Molecular and cellular biology.

[85]  M. Pfahl,et al.  Mutations that alter ligand-induced switches and dimerization activities in the retinoid X receptor , 1994, Molecular and cellular biology.

[86]  B. O’Malley,et al.  Ligand-dependent conformational changes in thyroid hormone and retinoic acid receptors are potentially enhanced by heterodimerization with retinoic X receptor , 1993, The Journal of Steroid Biochemistry and Molecular Biology.

[87]  J. Qin,et al.  Identity between TRAP and SMCC complexes indicates novel pathways for the function of nuclear receptors and diverse mammalian activators. , 1999, Molecules and Cells.

[88]  D. Barettino,et al.  Characterization of the ligand‐dependent transactivation domain of thyroid hormone receptor. , 1994, The EMBO journal.

[89]  J. Lehmann,et al.  Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. , 2000, Molecular cell.

[90]  S. Detera-Wadleigh,et al.  Phylogeny of the steroid receptor superfamily. , 1994, Molecular phylogenetics and evolution.

[91]  L. Jendeberg,et al.  Crystal Structure of the Ligand Binding Domain of the Human Nuclear Receptor PPARγ* , 1998, The Journal of Biological Chemistry.

[92]  William Bourguet,et al.  A canonical structure for the ligand-binding domain of nuclear receptors , 1996, Nature Structural Biology.

[93]  R. Evans,et al.  Mechanism of corepressor binding and release from nuclear hormone receptors. , 1999, Genes & development.

[94]  R J Fletterick,et al.  Hormone-dependent coactivator binding to a hydrophobic cleft on nuclear receptors. , 1998, Science.

[95]  The origin of nuclear receptor proteins: a single precursor distinct from other transcription factors. , 1992, Molecular endocrinology.

[96]  Peter J. Brown,et al.  Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ , 1997 .

[97]  M. Tanen,et al.  Analysis of the functional role of steroid receptor coactivator-1 in ligand-induced transactivation by thyroid hormone receptor. , 1997, Molecular Endocrinology.

[98]  M. Stallcup,et al.  Nuclear receptor-binding sites of coactivators glucocorticoid receptor interacting protein 1 (GRIP1) and steroid receptor coactivator 1 (SRC-1): multiple motifs with different binding specificities. , 1998, Molecular Endocrinology.

[99]  J. Gustafsson,et al.  Differential Response of Estrogen Receptor a and Estrogen Receptor b to Partial Estrogen Agonists/Antagonists , 1998 .

[100]  C. Glass,et al.  Co-activators and co-repressors in the integration of transcriptional responses. , 1998, Current opinion in cell biology.

[101]  V. Laudet,et al.  Evolution of the nuclear receptor gene superfamily. , 1992, The EMBO journal.

[102]  C. Glass,et al.  Determinants of coactivator LXXLL motif specificity in nuclear receptor transcriptional activation. , 1998, Genes & development.

[103]  M. Downes,et al.  Structure-function analysis of the Rev-erbA and RVR ligand-binding domains reveals a large hydrophobic surface that mediates corepressor binding and a ligand cavity occupied by side chains. , 2000, Molecular endocrinology.

[104]  K. Yamamoto,et al.  Crystallographic analysis of the interaction of the glucocorticoid receptor with DNA , 2003, Nature.

[105]  R J Fletterick,et al.  Structure and specificity of nuclear receptor-coactivator interactions. , 1998, Genes & development.

[106]  Christopher K. Glass,et al.  The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function , 1997, Nature.

[107]  R. Knegtel,et al.  The solution structure of the human retinoic acid receptor-β DNA-binding domain , 1993, Journal of biomolecular NMR.

[108]  C. Glass,et al.  A complex containing N-CoR, mSln3 and histone deacetylase mediates transcriptional repression , 1997, nature.

[109]  M. Lazar,et al.  Structural elements of an orphan nuclear receptor-DNA complex. , 1998, Molecular cell.

[110]  S. Kliewer,et al.  NMR Spectroscopic Studies of the DNA-binding Domain of the Monomer-binding Nuclear Orphan Receptor, Human Estrogen Related Receptor-2 , 1997, The Journal of Biological Chemistry.

[111]  S. Khorasanizadeh,et al.  Structure of the RXR–RAR DNA‐binding complex on the retinoic acid response element DR1 , 2000, The EMBO journal.

[112]  K. Umesono,et al.  Three-dimensional modeling of and ligand docking to vitamin D receptor ligand binding domain. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[113]  T. Smith,et al.  Homology model for the ligand-binding domain of the human estrogen receptor. , 1998, Journal of biomolecular structure & dynamics.

[114]  P. Sigler,et al.  DNA-binding mechanism of the monomeric orphan nuclear receptor NGFI-B , 1999, Nature Structural Biology.

[115]  David A. Agard,et al.  The Structural Basis of Estrogen Receptor/Coactivator Recognition and the Antagonism of This Interaction by Tamoxifen , 1998, Cell.

[116]  J. Lehmann,et al.  A peroxisome proliferator-activated receptor gamma ligand inhibits adipocyte differentiation. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[117]  P. Chambon,et al.  Oestradiol induction of a glucocorticoid-responsive gene by a chimaeric receptor , 1987, Nature.

[118]  Millard H. Lambert,et al.  Asymmetry in the PPARγ/RXRα Crystal Structure Reveals the Molecular Basis of Heterodimerization among Nuclear Receptors , 2000 .

[119]  M. Sierk,et al.  Structural basis of RXR-DNA interactions. , 2000, Journal of molecular biology.

[120]  R. Roeder,et al.  The TRAP220 component of a thyroid hormone receptor- associated protein (TRAP) coactivator complex interacts directly with nuclear receptors in a ligand-dependent fashion. , 1998, Proceedings of the National Academy of Sciences of the United States of America.