The objective of this research is to learn how DNA-binding domains (DBD) of control proteins recognize binding sites that are arranged tandemly (in the same direction) along the DNA duplex, rather than as antiparallel dimers that could be recognized by the two subunits of a dimeric protein. A superfamily of eukaryotic nuclear receptors has subunits consisting of three domains: an amino-terminal transactivation domain, a central DBD, and a carboxyl-terminal ligand-binding domain (LBD). The 9-cis retinoic acid receptor (RXR) can form a homodimer or, alternatively, can form heterodimers with a related all-trans retinoic acid receptor (RAR), thyroid hormone receptor (TR), or vitamin D3 receptor (VDR). The 6-base-pair tandem recognition sites on the DNA can be separated by as few as one intervening base pair (dr1), or as many as five base pairs (dr5). Interestingly enough, the information that is recognized by a given RXR dimer seems to be, not the base sequence of the sites themselves, which are the same in all cases, but the spacing between binding sites, dr1 - dr5. Dr. Rastinejad has already solved the crystal structure of the tandem complex of RXR and TR on sites separated by four base pairs, which will be designated as: RXR TR/dr4, and has begun to frame hypotheses concerning recognition and specificity. (Only the DBD of the various receptor proteins are involved at this stage of the work.) He plans to complete two ongoing structure analyses, of RXR RXR/dr1 and RXR RAR/dr1. He then plans to improve crystals of the RXR VDR/dr3 complex and solve its structure, and attempt to grow crystals of RXR RAR/dr2 and RXR RAR/dr5. From this work, he hopes to provide a mechanistic explanation of just how the DBD's, in different combinations, require different spacings between the two binding sites, or how these control proteins use geometry rather than base sequence as a recognition device.
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