Secondary literature sources for ZnF_C4
The following references were automatically generated.
- Zhao Q, Chasse SA, Devarakonda S, Sierk ML, Ahvazi B, Rastinejad F
- Structural basis of RXR-DNA interactions.
- J Mol Biol. 2000; 296: 509-20
- Display abstract
The 9-cis retinoic acid receptor, RXR, binds DNA effectively as a homodimer or as a heterodimer with other nuclear receptors. The DNA-binding sites for these RXR complexes are direct repeats of a consensus sequence separated by one to five base-pairs of intervening space. Here, we report the 2.1 A crystal structure of the RXR-DNA-binding domain as a homodimer in complex with its idealized direct repeat DNA target. The structure shows how a gene-regulatory site can induce conformational changes in a transcription factor that promote homo-cooperative assembly. Specifically, an alpha-helix in the T-box is disrupted to allow efficient DNA-binding and subunit dimerization. RXR displays a relaxed mode of sequence recognition, interacting with only three base-pairs in each hexameric half-site. The structure illustrates how site selection is achieved in this large eukaryotic transcription factor family through discrete protein-protein interactions and the use of tandem DNA binding sites with characteristic spacings.
- Zhao Q, Khorasanizadeh S, Miyoshi Y, Lazar MA, Rastinejad F
- Structural elements of an orphan nuclear receptor-DNA complex.
- Mol Cell. 1998; 1: 849-61
- Display abstract
The nuclear hormone receptors form the largest known family of transcription factors. The current notion of receptor DNA discrimination, based solely on one major type of hexameric half-site and a highly conserved 66-residue core DNA-binding domain (DBD), does not adequately describe how more than 150 nonsteroid receptors differentiate among response elements. Here, we describe the 2.3 A crystal structure of the DNA-binding region of the orphan receptor RevErb arranged as a tandem homodimer on its optimal response element. The structure reveals the presence of a second major protein-DNA interface adjacent to the classical one involving the half-sites. A sequence comparison of orphan receptors suggests that unique minor-groove interactions involving the receptor hinge regions impart the necessary DNA and dimerization specificity.
- Greisman HA, Pabo CO
- A general strategy for selecting high-affinity zinc finger proteins for diverse DNA target sites.
- Science. 1997; 275: 657-61
- Display abstract
A method is described for selecting DNA-binding proteins that recognize desired sequences. The protocol involves gradually extending a new zinc finger protein across the desired 9- or 10-base pair target site, adding and optimizing one finger at a time. This procedure was tested with a TATA box, a p53 binding site, and a nuclear receptor element, and proteins were obtained that bind with nanomolar dissociation constants and discriminate effectively (greater than 20,000-fold) against nonspecific DNA. This strategy may provide important information about protein-DNA recognition as well as powerful tools for biomedical research.
- Rhodes D, Schwabe JW, Chapman L, Fairall L
- Towards an understanding of protein-DNA recognition.
- Philos Trans R Soc Lond B Biol Sci. 1996; 351: 501-9
- Display abstract
Understanding how proteins recognize DNA in a sequence-specific manner is central to our understanding of the regulation of transcription and other cellular processes. In this article we review the principles of DNA recognition that have emerged from the large number of high-resolution crystal structures determined over the last 10 years. The DNA-binding domains of transcription factors exhibit surprisingly diverse protein architectures, yet all achieve a precise complementarity of shape facilitating specific chemical recognition of their particular DNA targets. Although general rules for recognition can be derived, the complex nature of the recognition mechanism precludes a simple recognition code. In particular, it has become evident that the structure and flexibility of DNA and contacts mediated by water molecules contribute to the recognition process. Nevertheless, based on known structures it has proven possible to design proteins with novel recognition specificities. Despite this considerable practical success, the thermodynamic and kinetic properties of protein/DNA recognition remain poorly understood.
- Dellovade TL, Zhu YS, Pfaff DW
- Potential interactions between estrogen receptor and thyroid receptors relevant for neuroendocrine systems.
- J Steroid Biochem Mol Biol. 1995; 53: 27-31
- Display abstract
Environmental signals can profoundly affect reproductive behavior, physiology and responses to steroids. One consequence of nutritional or temperature stress is altered plasma concentrations of thyroid hormone. Recent in vivo and in vitro data indicate that manipulations of estrogen and thyroid hormone levels can alter each other's functions. One possible mechanism for interaction may be that thyroid and estrogen receptors bind to parts of the same hormone response elements of target genes and compete with each other, thus serving to integrate environmental signals with neuroendocrine responses.
- Zilliacus J, Wright AP, Carlstedt-Duke J, Nilsson L, Gustafsson JA
- Modulation of DNA-binding specificity within the nuclear receptor family by substitutions at a single amino acid position.
- Proteins. 1995; 21: 57-67
- Display abstract
Regulation of gene expression involves a large number of transcription factors with unique DNA-binding properties. Many transcription factors belong to families of related proteins that bind to similar but distinct sequences. In this study we have analyzed how amino acid substitutions at a single position in the DNA-binding domain modulate the DNA-binding specificity within the nuclear receptor family of transcription factors. All possible amino acids were introduced at the first position in the DNA recognition helix, and the specificities of the mutants were analyzed using response elements containing all combinations of bases at two variable base pair positions. All mutant proteins were functional in DNA binding, and could be divided into classes of mutants with different response element specificities. By combining functional data with analysis of the structural effects of the mutations by molecular modeling, we could identify both prohibitive steric interactions as well as positive interactions, such as hydrogen bonds, that function as important determinants for specificity. Only the residues found naturally in the glucocorticoid and estrogen receptors, glycine and glutamate, produce unique binding specificities. The specificities of the other mutants overlap with each other somewhat but the substitutions clearly have potential to contribute to diversity within the nuclear receptor family.
- Hendry LB, Mahesh VB
- A putative step in steroid hormone action involves insertion of steroid ligands into DNA facilitated by receptor proteins.
- J Steroid Biochem Mol Biol. 1995; 55: 173-83
- Display abstract
The hypothesis is advanced that hormonal ligands in the steroid/thyroid superfamily act through insertion between base pairs in partially unwound DNA. Using published X-ray coordinates of the complex of the glucocorticoid hormone response element (GRE) with the glucocorticoid receptor DNA binding domain, the interface between the protein and the gene was examined. The site 5'-TG-3'-5'-CA-3' previously shown to accommodate cortisol was found in the first two bases of the GRE half sites, 5'-TGTTCT-3'. These base pairs were sufficiently exposed at the receptor-gene interface to permit access by the steroid. Docking of cortisol into the receptor/DNA complex resulted in a favorable van der Waals energy. Given the general lack of correlation of receptor binding with hormonal activity, we propose that hormone action involves an additional step in which the receptor protein in concert with other transcription factors inserts the hormone into the DNA. This notion provides an explanation for earlier paradoxical observations including structural analogies between base pairs and steroid hormones. The insertion hypothesis suggests that receptor bound ligand facilitates DNA unwinding, stereospecific control of donor/acceptor functional groups on the DNA followed by insertion and release of the ligand between base pairs at 5'-TG-3'-5'-CA-3'.
- Smit-McBride Z, Privalsky ML
- DNA sequence specificity of the v-erb A oncoprotein/thyroid hormone receptor: role of the P-box and its interaction with more N-terminal determinants of DNA recognition.
- Mol Endocrinol. 1994; 8: 819-28
- Display abstract
The viral erb A oncogene is a mutated allele of a normal cell gene for a thyroid hormone receptor. The DNA recognition properties of the v-erb A protein are altered from those of the thyroid hormone receptor, due in part to a point mutation in the P-box of the zinc-finger domain of the viral allele. We report here the effects of systematically varying this P-box codon; our results suggest that this P-box amino acid contributes to DNA specificity not by promoting recognition of the appropriate response elements, but rather by excluding binding of the erb A protein to inappropriate half-sites. In this manner, DNA recognition by the v-erb A protein appears to differ from that by the glucocorticoid receptor. A variety of P-box amino acids were compatible with recognition of the prototypic AGGTCA half-site; intriguingly, several of these mutant erb A proteins could also recognize a variety of alternative half-site sequences. Recognition of these alternative half-sites required a compatible amino acid sequence in the N terminus of the erb A protein. Our results begin to define a code by which the identity of the amino acids in the zinc-finger and N-terminal domains is reflected in the DNA recognition properties of the receptor.
- Pfahl M
- Vertebrate receptors: molecular biology, dimerization and response elements.
- Semin Cell Biol. 1994; 5: 95-103
- Display abstract
The nuclear receptors are a large family of ligand sensitive transcriptional regulators. They bind specific DNA sequences (response elements) in the promoter region of responsive genes. While the steroid hormone receptors bind as homodimers just two basic response elements, the retinoid and thyroid hormone receptor family interacts with a diverse set of response elements as homo- and heterodimers. The retinoid X receptors have a central role, since they form heterodimers with a whole subclass of receptors, consistent with the pleiotropic effects of retinoids. Differences in the mechanism of actions between steroid hormone receptors and other members of the family are discussed.
- Nelson CC, Hendy SC, Faris JS, Romaniuk PJ
- The effects of P-box substitutions in thyroid hormone receptor on DNA binding specificity.
- Mol Endocrinol. 1994; 8: 829-40
- Display abstract
Three "P-box" amino acids within the DNA recognition alpha-helix of members of the steroid hormone and thyroid hormone families of nuclear receptors are known to determine the identity of two of the six base pairs within the half-sites of cognate DNA elements. We introduced P-box substitutions derived from different members of the thyroid hormone/estrogen receptor (T3R/ER) family into the beta-isoform of human thyroid hormone receptor (hT3R beta) and tested the DNA binding and transactivation activities of these mutants using thyroid hormone response elements (TREs) with half-sites composed of different sequences and arranged in different orientations. Different P-box sequences derived from the T3R/ER family resulted in distinct DNA binding specificities determined by the fourth base pair of the half-site. Thyroid hormone receptor mutants containing EGA, EAA, EGS substitutions for the wild type EGG P-box bound with wild type affinity to consensus AGGTCA half-sites, regardless of orientation. TREs composed of AGGACA half-sites bound hT3R beta s with an EGG or EAA P-box sequence, but not those with EGA or EGS P-box sequence. A reversal of this specificity was observed on a direct repeat TRE with AGGGCA half-sites. Additionally, an ESG P-box substitution in hT3R beta prevented the receptor from binding to a direct repeat as a homodimer, but this mutant could bind as a heterodimer with retinoid X receptor or to the everted repeat TRE from the chicken lysozyme promoter.
- Zilliacus J, Carlstedt-Duke J, Gustafsson JA, Wright AP
- Evolution of distinct DNA-binding specificities within the nuclear receptor family of transcription factors.
- Proc Natl Acad Sci U S A. 1994; 91: 4175-9
- Display abstract
Nuclear receptors are ligand-activated transcription factors that interact with response elements within regulated genes. Most receptors, typified by the estrogen receptor, have three amino acids within the DNA-binding domain that specify recognition of the sequence TGACCT within the response element. However, in the glucocorticoid group of receptors, these residues have evolved to recognize the sequence TGTTCT. Saturation mutagenesis was used to investigate the role played by two of these residues (Gly-439 and Ser-440 of the human glucocorticoid receptor) in receptor specificity. We conclude that these residues, and their equivalents in the estrogen receptor, play roles unique to the respective amino acids. In the glucocorticoid receptor the side chain hydroxyl group is the important component of Ser-440 that contributes to specificity by inhibiting interaction with estrogen response elements. Several substitution mutants at position 439 interact well with estrogen response elements; therefore, the unique specificity feature of Glu-439, which mimics the estrogen receptor, is its inhibition of interaction with noncognate sites. In contrast to position 440, where most substitutions prevent interaction with DNA, replacements of residue 439 have the potential to contribute to the evolution of DNA-binding specificities within the nuclear receptor family. The liver-enriched HNF-4 and Drosophila Tailless transcription factors are known examples of receptors that have diverged at this position.
- Truss M, Beato M
- Steroid hormone receptors: interaction with deoxyribonucleic acid and transcription factors.
- Endocr Rev. 1993; 14: 459-79
- Display abstract
Gene regulation by steroid hormones is mediated by binding of the hormone ligand to the corresponding receptor that triggers a complex set of interactions of the hormone receptors with each other, with DNA in chromatin, and with a variety of other proteins. In this review we attempt to summarize what is known about these interactions using as the main example the regulation of mouse mammary tumor virus transcription by glucocorticoids and progestins. We describe in some detail the interaction of monomers and homodimers of the steroid receptors with their recognition sequences, and the molecular mechanism used to discriminate between the responsive elements for glucocorticoids/progestins and estrogens. We then review the interactions between homologous and heterologous hormone receptors on complex hormone regulatory regions, before devoting some attention to the synergistic and inhibitory interactions of hormone receptors with other transcription factors. Finally we briefly summarize some of the possible mechanisms that modulate the molecular interactions of hormone receptors. In addition to ligand binding, these include receptor phosphorylation, changes in DNA topology, and the organization of DNA in nucleosomes. From this overview we draw the tentative conclusion that the specificity of the hormonal response in different cells results from a combination of developmental restrictions both in the accessibility of genomic sequence and in the repertoire of regulatory proteins present in each particular cell. In addition, the array of regulatory sequences in DNA and chromatin determines the precise nature of macromolecular interactions of the receptors that are modulated by their degree of phosphorylation.
- Kothekar V
- Transcription regulation by steroid hormones: a computer simulation study.
- J Biomol Struct Dyn. 1992; 10: 49-62
- Display abstract
Three-dimensional structures of complexes of 66 amino acid-DNA binding domains of human progesterone (hPR), estrogen (hER) and glucocorticoid (hGR) receptors (proteins), with ten base pair DNA duplexes: d(AGGTCATGCT).d(AGCATGACCT) and d(AGAACATGCT).d(AGCATGTTCT) were obtained using computer modeling and molecular mechanics techniques. Cartesian coordinates for the proteins were obtained from: 1) structural data of hER and hGR by NMR spectroscopy; 2) steric constraints imposed by tetrahedral coordination of the zinc ion to Cys residues, and 3) energy minimization in torsional and cartesian space. The proteins were made to interact with DNA (in B-form) in major groove through alpha-helical linker between the two zinc fingers. The geometry of the complexes was obtained by allowing them to slide, glide, penetrate in to and out of the groove, and to rotate about the helical axis. The complexes were energy minimized. Also maximized was the number of H-bonds between proteins and DNA. The complex structures were refined by molecular mechanics using AMBER 3.0. Structural parameters of DNA were analyzed in each complex and compared with those of native DNA optimized separately. The stereochemical differences of the complexes are discussed.
- Jensen EV
- Steroid hormone receptors.
- Curr Top Pathol. 1991; 83: 365-431
- Display abstract
In the three decades since the original discovery of receptors for steroid hormones, much has been learned about the biochemical processes by which these regulatory agents exert their effects in target tissues. The intracellular receptor proteins are potential transcription factors, needed for optimal gene expression in hormone-dependent cells. They are present in an inactive form until association with the hormone converts them to a functional state that can react with target genes. Transformation of the receptor protein to the nuclear binding form appears to involve the removal of both macromolecular and micromolecular factors that act to keep the receptor form reacting with DNA. Much of the native receptor is present in the nucleus, loosely bound and readily extractable, but for some and possibly all steroid hormones, some receptor is in the cytoplasm, perhaps in equilibrium with a nuclear pool. Methods have been developed for the stabilization, purification, and characterization of receptor proteins, and through cloning and sequencing of their cDNAs, primary structures for these receptors are now known. This has led to the recognition of structural similarities among the family of receptors for the different steroid hormones and to the identification of regions in the protein molecule responsible for the various aspects of their function. Monoclonal antibodies recognizing specific molecular domains are available for most receptors. Despite the knowledge that has been acquired, many important questions remain unsolved. How does association with the steroid remove factors keeping the receptor protein in its native state, and how does binding of the transformed receptor to the response element in the promoter region enhance gene transcription? Once it has converted the receptor to the nuclear binding state, is there a further role for the steroid in modulating transcription? Still not entirely clear is the involvement of phosphorylation and/or dephosphorylation in hormone binding, receptor transformation, and transcriptional activation. Less vital to basic understanding but important in the overall picture is whether the native receptors for gonadal hormones are entirely confined to the nucleus or whether there is an intracellular distribution equilibrium. With the effort now being devoted to this field, and with the application of new experimental techniques, especially those of molecular biology, our understanding of receptor function is progressing rapidly. The precise mechanism of steroid hormone action should soon be completely established.
- Forman BM, Samuels HH
- Interactions among a subfamily of nuclear hormone receptors: the regulatory zipper model.
- Mol Endocrinol. 1990; 4: 1293-301
- Display abstract
The nuclear hormone receptors comprise a superfamily of ligand-modulated transcription factors that regulate homeostasis, reproduction, development, and differentiation. Three amino acids within the zinc finger DNA binding motif determine target gene specificity. Groups of receptors exist with similar DNA binding specificity. A complex carboxy terminal region mediates ligand binding, dimerization, and hormone-relieved transcriptional inactivation. We summarize the current understanding of these phenomena and suggest a novel model that structurally and functionally links these events. This "regulatory zipper model" may explain the mechanism by which ligand activates nuclear hormone receptors.
- Schwabe JW, Neuhaus D, Rhodes D
- Solution structure of the DNA-binding domain of the oestrogen receptor.
- Nature. 1990; 348: 458-61
- Display abstract
Steroid hormone receptors control gene expression through binding, as dimers, to short palindromic response elements located upstream of the genes they regulate. An independent domain of approximately 70 amino acids directs this sequence-specific DNA binding and is highly conserved between different receptor proteins and related transcription factors. This domain contains two zinc-binding Cys2-Cys2 sequence motifs, which loosely resemble the 'zinc-finger' motifs of TFIIIA. Here we describe the structure of the DNA-binding domain from the oestrogen receptor, as determined by two-dimensional 1H NMR techniques. The two 'zinc-finger'-like motifs fold to form a single structural domain and are thus distinct from the independently folded units of the TFIIIA-type zinc fingers. The structure consists of two helices perpendicular to each other. A zinc ion, coordinated by four conserved cysteines, holds the base of a loop at the N terminus of each helix. This novel structural domain seems to be a general structure for protein-DNA recognition.
- Picard D, Kumar V, Chambon P, Yamamoto KR
- Signal transduction by steroid hormones: nuclear localization is differentially regulated in estrogen and glucocorticoid receptors.
- Cell Regul. 1990; 1: 291-9
- Display abstract
The glucocorticoid receptor accumulates in nuclei only in the presence of bound hormone, whereas the estrogen receptor has been reported to be constitutively nuclear. To investigate this distinction, we compared the nuclear localization domains of the two receptors and the capacity of their respective hormone-binding regions to regulate nuclear localization activity. As with the glucocorticoid receptor, we showed that the human estrogen receptor contained a nuclear localization signal between the DNA-binding and hormone-binding regions (amino acids 256-303); however, in contrast to the glucocorticoid receptor, the estrogen receptor lacked a second nuclear localization domain within the hormone-binding region. Moreover, the hormone-binding domain of the unliganded estrogen receptor failed to regulate nuclear localization signals, although it efficiently regulated other receptor functions. We conclude that the two receptors employ a common mechanism for signal transduction involving a novel "inactivation" function, but that they differ in their control of nuclear localization. Thus, despite the strong relatedness of the estrogen and glucocorticoid receptors in structure and activity, certain differences in their properties could have important functional implications.
- Green S, Chambon P
- Chimeric receptors used to probe the DNA-binding domain of the estrogen and glucocorticoid receptors.
- Cancer Res. 1989; 49: 22822285-22822285
- Display abstract
Steroid hormone receptors activate specific gene transcription by binding as hormone-receptor complexes to short DNA enhancer-like elements termed hormone response elements. The DNA-binding domain (termed region C) is a highly conserved 66-amino acid region that contains two subregions (CI and CII) analogous to the "zinc fingers" of transcription factor IIIA. Using chimeric estrogen receptors, we show that this region, and in particular the NH2-terminal zinc finger, defines the target gene specificity of the receptor. We suggest that receptor recognition of the hormone response element is analogous to that of the helix-turn-helix DNA-binding motif in that the receptor binds to DNA as a dimer with the first zinc finger lying in the major groove recognizing one-half of the palindromic hormone response element and protein-DNA interaction is stabilized through nonspecific DNA binding and dimer interactions contributed by the second zinc finger.
- Miesfeld RL
- The structure and function of steroid receptor proteins.
- Crit Rev Biochem Mol Biol. 1989; 24: 101-17
- Display abstract
This review has highlighted several topics in the study of steroid hormone action. The unanswered questions regarding the mechanism of ligand-controlled LRF activity, the extent of evolutionary conservation and specificity of DNA binding, and the validity of various models of transcriptional regulation mediated through gene networks point to the future direction of research in this field. Steroid hormones are used extensively in clinical treatments, especially glucocorticoids. Our laboratory is attempting to determine which gene networks are responsible for some of these clinical phenotypes. Figure 5 points out that the study of glucocorticoid action holds a unique position because it spans both the basic sciences and the field of applied molecular biology. Now that we have a fundamental knowledge of the necessary elements required for steroid-dependent regulation of gene expression, we can better investigate the clinical responses to steroid therapy (which include devastating side effects) by isolating and characterizing the important target gene(s). In this author's opinion, future directions in the study of steroid responsiveness will have to include a systematic approach toward deciphering a variety of these LRF-regulated gene networks in experimentally feasible systems. Hopefully, work in this area may be revealing and perhaps beneficial to ongoing clinical studies. In addition, the study of mechanisms of transcriptional induction and repression, using the model system of LRFs, could be applicable to many gene regulatory systems which are controlled by such processes as development and differentiation.
- Umesono K, Evans RM
- Determinants of target gene specificity for steroid/thyroid hormone receptors.
- Cell. 1989; 57: 1139-46
- Display abstract
The molecular specificity of the receptors for steroid and thyroid hormones is achieved by their selective interaction with DNA binding sites referred to as hormone response elements (HREs). HREs can differ in primary nucleotide sequence as well as in the spacing of their dyadic half-sites. The target gene specificity of the glucocorticoid receptor can be converted to that of the estrogen receptor by changing three amino acids clustered in the first zinc finger. Remarkably, a single Gly to Glu change in this region produces a receptor that recognizes both glucocorticoid and estrogen response elements. Further replacement of five amino acids in the stem of the second zinc finger transforms the specificity to that of the thyroid hormone receptor. These findings localize structural determinants required for discrimination of HRE sequence and half-site spacing, respectively, and suggest a simple pathway for the coevolution of receptor DNA binding domains and hormone-responsive gene networks.
- Brendel V, Karlin S
- Association of charge clusters with functional domains of cellular transcription factors.
- Proc Natl Acad Sci U S A. 1989; 86: 5698-702
- Display abstract
Using rigorous statistical methods, we have identified and evaluated unusual properties of the distribution of charged residues within the sequences of eukaryotic cellular transcription factors. Virtually all transcription factors, including GAL4, c-Jun, C/EBP, CREB, Oct-1, Oct-2, Sp1, Egr-1, CTF-1, steroid and thyroid hormone receptors, and others, carry one or more highly significant charge clusters. For the most part these clusters (conserved within families of homologous proteins) are of positive net charge but contain also substantial numbers of acidic residues. Predominantly basic charge clusters are often, but not exclusively, associated with DNA-binding domains, and vice versa. Negative charge clusters of note occur only in the yeast protein PHO4 and in the proteins encoded at the Drosophila loci zeste (zeta) and knrl. This dearth of statistically significant negative charge clusters raises questions with respect to the generality of acidic activation domains. A number of sequences (Oct-1, Oct-2, zeste, Dhr23, E75, and knrl) contain multiple charge clusters together with one or more significantly long uncharged regions. The occurrence of multiple charge clusters is a rare phenomenon (found in less than 3% of all proteins, mainly in Drosophila developmental control proteins and in transactivators of eukaryotic DNA viruses). Most of the proteins with zinc-binding "fingers" carry a mixed charge cluster centered at the zinc-finger motif preceded by a long uncharged stretch, suggestive of a modular structure for these proteins.
- Sakai M
- [Steroid receptors: domain structure and gene regulation]
- Nippon Rinsho. 1989; 47: 2316-23
- Giguere V, Yang N, Segui P, Evans RM
- Identification of a new class of steroid hormone receptors.
- Nature. 1988; 331: 91-4
- Display abstract
The gonads and adrenal glands produce steroids classified into five major groups which include the oestrogens, progestins, androgens, glucocorticoids and mineralocorticoids. Gonadal steroids control the differentiation and growth of the reproductive system, induce and maintain sexual characteristics and modulate reproductive behaviour. Adrenal steroids also influence differentiation as well as being metabolic regulators. The effects of each steroid depend primarily on its specific receptors, the nature of which could therefore provide a basis for classification of steroid hormone action. The successful cloning, sequencing and expression of the human glucocorticoid (hGR) (ref. 1), oestrogen (hER), progesterone (hPR), and mineralocorticoid (hMR) receptors, complementary DNA, plus homologues from various species, provides the first opportunity to study receptor structure and its influence on gene expression. Sequence comparison and mutational analysis show structural features common to all groups of steroid hormone receptors. The receptors share a highly conserved cysteine-rich region which functions as the DNA-binding domain. This common segment allows the genome to be scanned for related gene products: hMR cDNA for example, was isolated using an hGR hybridization probe. In this study, using the DNA-binding domain of the human oestrogen receptor cDNA as a hybridization probe, we have isolated two cDNA clones encoding polypeptides with structural features suggestive of cryptic steroid hormone receptors which could participate in a new hormone response system.
