We report the first quantification of Cul3 binding to a protein of the KCTD family.
MD simulations highlight the regions involved in Cul3-KCTD interactions.
KCTD5-Cul3 recognition is characterized by a high level structural complexity.
Homology modeling indicates that INC interacts with Cul3 using a similar mechanism.
The architecture of the entire KCTD5-containing E3 ligase system has been analyzed.