Modifying ligand specificity of gene regulatory proteins

Current Opinion in Chemical Biology

Volumn 4, Issue 1, 2000, Pages 60-64

  Doyle, Donald F ^a   Mangelsdorf, David J ^a   Corey, David R ^a  

^a HOWARD HUGHES MEDICAL INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALITRETINOIN; CELL NUCLEUS RECEPTOR; ECDYSONE; ESTROGEN RECEPTOR; PROGESTERONE RECEPTOR; REGULATOR PROTEIN; RETINOIC ACID; RETINOID X RECEPTOR;

GENE; GENE ACTIVATION; GENE EXPRESSION; GENE EXPRESSION REGULATION; GENETIC ENGINEERING; HUMAN; HYDROPHOBICITY; LIGAND BINDING; MUTAGENESIS; NONHUMAN; PROTEIN MODIFICATION; REVIEW;

ANIMALS; ECDYSONE; ESTROGENS; GLUCOCORTICOIDS; LIGANDS; MUTAGENESIS; NUCLEAR PROTEINS; PROGESTERONE; PROTEIN ENGINEERING; RECEPTORS, CELL SURFACE; TRETINOIN;

EID: 0033952559     PISSN: 13675931     EISSN: None     Source Type: Journal    
DOI: 10.1016/S1367-5931(99)00052-6     Document Type: Review

References (24)

1. Mangelsdorf D.J., Thummel C., Beato M., Herrlich P., Schütz G., Umesono K., Blumberg B., Kastner P., Mark M., Chambon P.et al. The nuclear receptor superfamily: the second decade. Cell. 83:1995;835-839.
2. No D., Yao T.P., Evans R.M. Ecdysone-inducible gene expression in mammalian cells. Proc Natl Acad Sci USA. 93:1996;3346-3351.
3. Martinez A., Sparks C., Drayton P., Thompson J., Greenland A., Jepson I. Creation of ecdysone receptor chimeras in plants for controlled regulation of gene expression. Mol Gen Genet. 261:1999;546-552.
4. Renaud J.P., Rochel N., Ruff M., Vivat V., Chambon P., Gronemeyer H., Moras D. Crystal structure of the RARγ ligand-binding domain bound to all-trans retinoic acid. Nature. 378:1995;681-689.
5. •]).
6. Bourguet W., Ruff M., Chambon P., Gronemeyer H., Moras D. Crystal structure of the ligand-binding domain of the human nuclear receptor RXRa. Nature. 375:1995;377-382.
7. Peet D.J., Doyle D.F., Corey D.R., Mangelsdorf D.J. Engineering novel specificities for ligand-activated tramscription in the nuclear hormone receptor RXR. Chem Biol. 5:1998;13-21. Structure-based site-directed mutagenesis of Phe313 and Leu436 of RXR changes the ligand binding specificity in two ways. The first class of variants activates transcription in response to 9cRA but not synthetic agonists. The second class activates transcription at low concentrations of synthetic agonists but has greatly reduced affinity for 9cRA.
8. Benhamou B., Garcia T., Lerouge T., Vergezac A., Gofflo D., Bigogne C., Chambon P., Gronemeyer H. A single amino acid that determines the sensitivity of progesterone receptors to RU486. Science. 255:1992;206-209.
9. Koh J.T., Putnam M., Tomic-Canic M., McDaniel C.M. Selective regulation of gene expression using rationally-modified retinoic acid receptors. J Am Chem Soc. 121:1999;1984-1985. Structure-based mutagenesis of human RARγ enables activation of transcription by ligands of opposite or neutral charge. Wild-type RARγ is activated by atRA (negatively charged). The double mutant variant Ser289Gly Arg278Glu is activated by the N-ethyl amide of retinoic acid (neutral charge). The variant Ser289Asp is activated by a guanyl analogue of retinoic acid (positively charged).
10. Hwang J-K., Warshel A. Why ion pair reversal by protein engineering is unlikely to succeed. Nature. 334:1988;270-272.
11. Gehin M., Vivat V., Wurtz J.M., Losson R., Chambon P., Moras D., Gronemeyer H. Structural basis for engineering of retinoic acid receptor isotype-selective agonists and antagonists. Chem Biol. 6:1999;519-529.
12. Cosman F., Lindsay R. Selective estrogen receptor modulators: clinical spectrum. Endocr Rev. 20:1999;418-434.
13. Katzenellenbogen J.A. The structural pervasiveness of estrogenic activity. Environ Health Perspect. 103:1995;99-101.
14. Brocard J., Warot X., Wendling O., Messaddeq N., Vonesch J.L., Chambon P., Metzger D. Spatio-temporally controlled site-specific somatic mutagenesis in the mouse. Proc Natl Acad Sci USA. 94:1997;14559-14563.
15. Wrenn C.K., Katzenellenbogen B.S. Structure-function analysis of the hormone binding domain of the human estrogen receptor by region-specific mutagenesis and phenotypic screening in yeast. J Biol Chem. 268:1993;24089-24098.
16. Ekena K., Katzenellenbogen J.A., Katzenellenbogen B.S. Determinants of ligand specificity of estrogen receptor-alpha: estrogen versus androgen discrimination. J Biol Chem. 273:1998;693-699.
17. Fink B.E., Mortensen D.S., Stauffer S.R., Aron Z.D., Katzenellenbogen J.A. Novel structural templates for estrogen-receptor ligands and prospects for combinatorial synthesis of estrogens. Chem Biol. 6:1999;205-219.
18. Eng F.C.S., Lee H.S., Ferrara J., Willson T.M., White J.H. Probing the structure and function of the estrogen receptor ligand binding domain by analysis of mutants with altered transactivation characteristics. Mol Cell Biol. 17:1997;4644-4653.
19. Burcin M.M., Schiedner G., Kochanek S., Tsai S.Y., O'Malley B.W. Adenovirus-mediated regulable target gene expression in vivo. Proc Natl Acad Sci USA. 96:1999;355-360. The system described here is based on the mifepristone-truncated PR system fused with the activation domain from a human protein. The advance in this paper is the use of a high capacity adenoviral vector to deliver both the receptor and reporter genes and use of a human activation domain to reduce possible immune responses in humans. Liver-specific expression of the reporter gene in mice is achieved by using a liver-specific promoter to control expression of the engineered nuclear receptor.
20. Wang Y., DeMayo F.J., Tsai S.Y., O'Malley B.W. Ligand-inducible and liver-specific target gene expression in transgenic mice. Nat Biotechnol. 15:1997;239-243.
21. •]. In this study, the receptor and reporter genes are on separate plasmids and delivered to the targeted mouse hind-limb muscles by direct injection followed by noninvasive electroporation. Levels of the reporter protein induced by mifepristone are equal to or higher than levels of reporter attained by the constitutively active cytomegalovirus promoter. However, the current system suffers from a high basal expression of reporter.
22. Lind U., Greenidge P., Gustafsson J.A., Wright A.P.H., Carlstedt-Duke J. Valine 571 functions as a regional organizer in programming the glucocorticoid receptor for differential binding of glucocorticoids and mineralocorticoids. J Biol Chem. 274:1999;18515-18523.
23. Norman T.C., Smith D.L., Sorger P.K., Drees B.L., O'Rourke S.M., Hughes T.R., Roberts C.J., Friend S.H., Fields S., Murray A.W. Genetic selection of peptide inhibitors of biological pathways. Science. 285:1999;591-595.
24. Norris J.D., Paige L.A., Christensen D.J., Chang C-Y., Huacani M.R., Fan D., Hamilton P.T., Fowlkes D.M., McDonnell D.P. Peptide antagonists of the human estrogen receptor. Science. 285:1999;744-746. The authors of this paper use phage display to select peptides that interact with either estradiol-activated or tamoxifen-activated ER. When expressed in cells, the peptides are ligand-specific antagonists. The results indicate that the estradiol-ER and tamoxifen-ER structures are functionally different. This is a new method of selectively antagonizing expression of ER-regulated genes. It will be interesting to see if the method will work on other nuclear receptors.