Fig. 4: Cryo-EM structures reveal HDAC2 as the direct interactor of UM171 and neomorphic mutants of KBTBD4.

a Cryo-EM map of the 2:2 KBTBD4^R313PRR-HDAC2 complex coloured by individual subunit (contour level = 0.15). BTB-BACK and Kelch regions in KBTBD4 are labelled. b Ribbon representation of the 2:2 KBTBD4^R313PRR-HDAC2 structure with each subunit coloured as in a. The dimer interface α1 and β1 in the KBTBD4 BTB domain are labelled. c Domain organizations of KBTBD4^WT, KBTBD4^R313PRR and HDAC2. d–f Cryo-EM maps of UM171-induced KBTBD4^WT-substrate complexes at 2:1 (KBTBD4:HDAC2, contour level = 0.08), 2:1:1 (KBTBD4:HDAC2:CoREST1, contour level = 0.08) and 2:2 (KBTBD4:HDAC2, contour level = 0.08). UM171 is coloured in yellow. Asterisk indicates the unoccupied central pocket of the KBTBD4 Kelch domain. g Ribbon representation of the KBTBD4^WT homodimer binding to UM171 and HDAC2. Subunits are coloured as in d–f. Each HDAC2 subunit interacts with residues at sites 1 and 2 in the KBTBD4 dimer as boxed and labelled by text. The distance between the two Kelch domains is measured by the side chains of E381. The interaction interface between the N-terminus of KBTBD4 chain a and the Kelch domain of KBTBD4 chain b is indicated with a red box. h Close-up view of the interaction interface between the N-terminus of KBTBD4 chain a and the Kelch domain of KBTBD4 chain b. KBTBD4 chains are coloured as in g and shown in ribbon representation. Key interacting residues are shown in sticks.