The human cofactor complexes ARC (activator-recruited cofactor) and CRSP 
(cofactor required for Sp1 activation) mediate activator-dependent transcription 
in vitro. Although these complexes share several common subunits, their 
structural and functional relationships remain unknown. Here, we report that 
affinity-purified ARC consists of two distinct multisubunit complexes: a larger 
complex, denoted ARC-L, and a smaller coactivator, CRSP. Reconstituted in vitro 
transcription with biochemically separated ARC-L and CRSP reveals differential 
cofactor functions. The ARC-L complex is transcriptionally inactive, whereas the 
CRSP complex is highly active. Structural determination by electron microscopy 
(EM) and three-dimensional reconstruction indicate substantial differences in 
size and shape between ARC-L and CRSP. Moreover, EM analysis of independently 
derived CRSP complexes reveals distinct conformations induced by different 
activators. These results suggest that CRSP may potentiate transcription via 
specific activator-induced conformational changes.