We use X-ray crystallography and other biophysical stufies to visualize transcription factors in their revealing complexes and assemblies. The nuclear hormone receptors are the largest known superfamily of eukaryotic transcription factors, with nearly 200 distinct members. In some cases, the receptors act as combinatorial transcription factors by forming pairwise interactions on DNA control sites. The combinatorial assemblies produce a cooperative enhancement in DNA affinity and facilitate the binding of coactivators and corepressors to the control sites. Hormone-responsive genes are regulated by the nuclear receptors in responsive lipophilic molecules like stereoids, retinoids, thyroid hormone, vitamin D3, and other molecules. Our work is directed at understanding 1) the stereochemical basis for DNA target recognition, and 2) the determinants of hormone binding to the receptor ligand-binding domain. our work on the DNA-complexes has resulted in high-resolution crystal structures of the following homodimers and heterodimers of the 9-cis retinoic acid receptor (RXR) with DNA: RXR-TR, RXR-RXR, RXR-RAR. In addition, we have solved the structure of the DNA-binding homodimeric complex of the orphan receptor RevErb. To understand the basis for ligand specificity, we have over-expressed a number of receptor ligand-binding domains and are pursuing co-crystallization studies with these polypeptides bound to their cognate ligands.

Selected References

Allison TJ, Wood TC, Briercheck DM, Rastinejad F, Richardson JP, Rule GS. (1998) "Crystal structure of the RNA-binding domain from transcription termination factor rho." Nat Struct Biol. 5:352-6. [PubMed]

Zhao Q, Khorasanizadeh S, Miyoshi Y, Lazar MA, Rastinejad F. (1998) "Structural elements of an orphan nuclear receptor-DNA complex." Mol Cell. 1:849-61. [PubMed]

Khorasanizadeh S, Rastinejad F. (1999) "Transcription factors: the right combination for the DNA lock." Curr Biol. Jun 9(12):R456-8. [PubMed]

Zhao Q, Chasse SA, Devarakonda S, Sierk ML, Ahvazi B, Rastinejad F. (2000) "Structural basis of RXR-DNA interactions." J Mol Biol. Feb 296:509-20. [PubMed]

Rastinejad F, Wagner T, Zhao Q, Khorasanizadeh S. (2000) "Structure of the RXR-RAR DNA-binding complex on the retinoic acid response element DR1." EMBO J. Mar 19:1045-54. [PubMed]

Wright CS, Li SC, Rastinejad F. (2000) "Crystal structure of human GM2-activator protein with a novel beta-cup topology." J Mol Biol. Dec 304:411-22. [PubMed]

Rastinejad F. (2001) "Retinoid X receptor and its partners in the nuclear receptor family." Curr Opin Struct Biol. 11:33-8. [PubMed]

Khorasanizadeh S, Rastinejad F. (2001) "Nuclear-receptor interactions on DNA-response elements." Trends Biochem Sci. 26:384-90. [PubMed]