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Homeodomain-only protein (HOP) is an 8-kDa transcriptional corepressor that is essential for the normal development of the mammalian heart. A combination of sequence comparison and our structural data revealed that HOP consists entirely of a homeodomain, and it is the only human protein to have this topology. We have also shown that, unlike other classic homeodomain proteins, HOP does not appear to interact with DNA, and it appears that it instead functions as a bridge in the formation of HDAC-type repressive complexes on DNA. However, the mechanism by which this repression occurs is still only partially resolved. Our results demonstrate that the homeodomain fold has been co-opted during evolution for functions other than sequence-specific DNA binding.