DNA RECOGNITION BY THE ESTROGEN-RECEPTOR - FROM SOLUTION TO THE CRYSTAL

Background: The steroid/nuclear hormone receptors are a large family o f conserved ligand-activated transcription factors that regulate gene expression through binding to response elements upstream of their targ et genes. Most members of this family bind to DNA as homodimers or het erodimers and recognize the sequence, spacing and orientation of the m io half-sites of their response elements. The recognition and discrimi nation of the sequence and arrangements of these half-sites are mediat ed primarily by a highly conserved DNA-binding domain. Results: Here w e describe the DNA-binding properties of the isolated DNA-binding doma in of the oestrogen receptor, the ERDBD, and its refined NMR structure . This domain is monomeric in solution, but two molecules bind coopera tively to specific DNA sequences; this cooperativity determines the ar rangement of half-sites that is recognized by the ERDBD. The 10 carbox y-terminal residues and a region of 15 residues within the domain are disordered in the solution structure, yet are important for DNA bindin g. Conclusion: The cooperative nature of ERDBD binding to DNA is impor tant. The previously-determined X-ray structure of the ERDBD dimer bou nd to DNA shows that the 15 internal residues disordered in solution m ake contact both with DNA and with the corresponding region of the oth er monomer. These results suggest that these residues become ordered d uring the process of binding to DNA, forming the dimer interface and t hus contributing to the cooperative interaction between monomers.