Despite having caused one of the greatest medical catastrophies of the last 
century through its teratogenic side-effects, thalidomide continues to be an 
important agent in the treatment of leprosy and cancer. The protein cereblon, 
which forms an E3 ubiquitin ligase compex together with damaged DNA-binding 
protein 1 (DDB1) and cullin 4A, has been recently indentified as a primary 
target of thalidomide and its C-terminal part as responsible for binding 
thalidomide within a domain carrying several invariant cysteine and tryptophan 
residues. This domain, which we name CULT (cereblon domain of unknown activity, 
binding cellular ligands and thalidomide), is also found in a family of secreted 
proteins from animals and in a family of bacterial proteins occurring primarily 
in δ-proteobacteria. Its nearest relatives are yippee, a highly conserved 
eukaryotic protein of unknown function, and Mis18, a protein involved in the 
priming of centromeres for recruitment of CENP-A. Searches for distant homologs 
point to an evolutionary relationship of CULT, yippee, and Mis18 to proteins 
sharing a common fold, which consists of two four-stranded β-meanders packing at 
a roughly right angle and coordinating a zinc ion at their apex. A β-hairpin 
inserted into the first β-meander extends across the bottom of the structure 
towards the C-terminal edge of the second β-meander, with which it forms a 
cradle-shaped binding site that is topologically conserved in all members of 
this fold. We name this the β-tent fold for the striking arrangement of its 
constituent β-sheets. The fold has internal pseudosymmetry, raising the 
possibility that it arose by duplication of a subdomain-sized fragment.