The retinoid X receptor (RXR) is a member of the nuclear hormone receptor superfamily and has recently been shown to function in a variety of hormonal signaling pathways by virtue of its ability to heterodimerize with other nuclear hormone receptors. Here we describe resonance assignments, the secondary structural elements and the global folding pattern of the DNA-binding domain (residues 130-223) of human RXR alpha, as determined by multidimensional nuclear magnetic resonance spectroscopy. Its overall structure is similar to those reported for the glucocorticoid, estrogen, and retinoic acid receptors, in that the two zinc fingers of RXR fold to form a single structural domain containing two helices, which are located at the carboxy terminal of the two zinc fingers. There is also a short antiparallel beta-sheet formed between two residues in the amino-terminal base of the first finger and two residues in the carboxy terminal of that same finger just before the first helix. However, in contrast to the other nuclear hormone receptor DNA-binding domains, the RXR domain contains a third helix immediately after the conserved Gly-Met sequence that signals the termination of the second helix. The second and third helices lie orthogonal to and wrap around the first helix, generating an extended hydrophobic core. Since helices two and three are separated by only two residues, the backbone flexibility afforded by the presence of the conserved glycine residue between them may be crucial for the proper positioning of the third helix relative to the first helix. A 12-amino-acid region termed the 'T-box', which includes this third helix, was recently shown to be required for homodimeric binding of RXR to its cognate response element [Wilson, T. E., Paulsen, R. E., Padgett, K. A. & Milbrandt, J. (1992) Science 256, 107-110].