Meyer-Almes - LOEWE - TRABITA

LOEWE-Schwerpunkt "Transiente Bindungstaschen" (2020-2023)

Overlay of crystal structures of HDAC4 in open (magenta, PDB-ID 2VQJ) and closed (green, PDB-ID 4CBY) conformation. The structural zinc binding domain undergoes substantial movements as indicated by the yellow arrow.

HDAC4 as model system for proteins with a flexible domain

Histondeacetylase 4 (HDAC4) is an established target for neurodegenerative diseses, particularly Huntington's disease and several types of cancer. At the bottom of the highly conserved active site pocket of zinc-dependent histone deacetylases (HDACs), there is a small transient side pocket. More strikingly and unlike class I HDACs, class IIa member HDAC4 contains a second structural zinc binding domain that undergoes substantial movements between an open- and closed conformation depending on binding of inhibitors with distinct chemical structures. Only the closed conformation can be recognized by the SMRT-corepressor thus transmitting the biological signal.