The BTB domain (also known as the POZ domain) is an evolutionarily conserved protein-protein interaction motif found at the N terminus of 5-10% of C 2 H 2 -type zinc-finger transcription factors, as well as in some actinassociated proteins bearing the kelch motif. Many BTB proteins are transcriptional regulators that mediate gene expression through the control of chromatin conformation. In the human promyelocytic leukemia zinc finger (PLZF) protein, the BTB domain has transcriptional repression activity, directs the protein to a nuclear punctate pattern, and interacts with components of the histone deacetylase complex. The association of the PLZF BTB domain with the histone deacetylase complex provides a mechanism of linking the transcription factor with enzymatic activities that regulate chromatin conformation. The crystal structure of the BTB domain of PLZF was determined at 1.9 Å resolution and reveals a tightly intertwined dimer with an extensive hydrophobic interface. Approximately one-quarter of the monomer surface area is involved in the dimer intermolecular contact. These features are typical of obligate homodimers, and we expect the fulllength PLZF protein to exist as a branched transcription factor with two C-terminal DNA-binding regions. A surfaceexposed groove lined with conserved amino acids is formed at the dimer interface, suggestive of a peptide-binding site. This groove may represent the site of interaction of the PLZF BTB domain with nuclear corepressors or other nuclear proteins.The BTB domain (Broad-Complex, Tramtrack, and Bric à brac) (1, 2), also known as POZ (poxvirus and zinc finger) (3), is an evolutionarily conserved protein-protein interaction domain often found in developmentally regulated transcription factors. The domain is strongly implicated in the regulation of gene expression through the local control of chromatin conformation (4). The domain was first identified in a set of Drosophila and poxvirus genes (5), and examples of BTB domain genes have since been found in organisms ranging from yeast to man.A search of the current publicly available sequence databases reveals 56 distinct human BTB entries, of which 22 correspond to named, full-length genes, whereas the remaining entries are known only as tentative human consensus (THC) sequences, or expressed sequence tags (EST), (a tabulation of these genes can be found at http:͞͞xtal.oci.utoronto.ca͞prive͞ btbtable.html). Approximately two-thirds of the full-length human BTB genes also encode C 2 H 2 zinc finger modules, whereas approximately one-half of the remaining entries contain the kelch motif (4, 6). None of the known human BTB genes contain more than one single copy of the domain, making it likely that most, if not all, of the known BTB tentative human consensus (THC) and expressed sequence tag (EST) entries correspond to distinct genes. Based on the projection that there are 300-700 zinc finger proteins in man (7), we estimate that 5-10% of zinc finger proteins also contain BTB domains. The domain is known to form h...