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.
- Frühauf A, Meyer-Almes FJ, Non-Hydroxamate Zinc-Binding Groups as Warheads for Histone Deacetylases, Molecules (2021) 26:5151.
- Tilekar K, Hess JD, Upadhyay N, Bianco AL, Schweipert M, Laghezza A, Loiodice F, Meyer-Almes FJ, Aguilera RJ, Lavecchia A, Ramaa CS. Thiazolidinedione “Magic Bullets” Simultaneously Targeting PPARγ and HDACs: Design, Synthesis, and Investigations of their In Vitro and In Vivo Antitumor Effects. J Med Chem (2021) 64:6949-6971.
- K. Tilekar, J. D. Hess, N. Upadhyay, M. Schweipert, F. Flath, D. A. Gutierrez, F. Loiodice, A. Lavecchia, F.-J. Meyer-Almes, R. J. Aguilera, R. C S, HDAC4 Inhibitors with Cyclic Linker and Non-hydroxamate Zinc Binding Group: Design, Synthesis, HDAC Screening and in vitro Cytotoxicity evaluation, Chemistry Select (2021) 6:6748-6763.
- Neha Upadhyay, Kalpana Tilekar, Sabreena Safuan, Alan P. Kumar, Markus Schweipert, Franz-Josef Meyer-Almes, Ramaa C S; Multi-target weapons: diaryl-pyrazoline thiazolidinediones simultaneously targeting VEGFR-2 and HDAC cancer hallmarks; RSC Med Chem 2021, accepted, https://doi.org/10.1039/ D1MD00125F