6H39
Yeast 20S proteasome in complex with the peptidic non-covalent binding inhibitor RTS-V5
Summary for 6H39
| Entry DOI | 10.2210/pdb6h39/pdb |
| Descriptor | Proteasome subunit alpha type-2, Proteasome subunit beta type-4, Proteasome subunit beta type-5, ... (20 entities in total) |
| Functional Keywords | hydrolase-hydrolase inhibitor complex, proteasome, histone-deacetylase, dual binding inhibitor, binding analysis, hydrolase |
| Biological source | Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast) More |
| Total number of polymer chains | 28 |
| Total formula weight | 732998.52 |
| Authors | Groll, M.,Hansen, F.K. (deposition date: 2018-07-17, release date: 2018-11-07, Last modification date: 2024-01-17) |
| Primary citation | Bhatia, S.,Krieger, V.,Groll, M.,Osko, J.D.,Reßing, N.,Ahlert, H.,Borkhardt, A.,Kurz, T.,Christianson, D.W.,Hauer, J.,Hansen, F.K. Discovery of the First-in-Class Dual Histone Deacetylase-Proteasome Inhibitor. J. Med. Chem., 61:10299-10309, 2018 Cited by PubMed Abstract: Dual- or multitarget drugs have emerged as a promising alternative to combination therapies. Proteasome inhibitors (PIs) possess synergistic activity with histone deacetylase (HDAC) inhibitors due to the simultaneous blockage of the ubiquitin degradation and aggresome pathways. Here, we present the design, synthesis, binding modes, and anticancer properties of RTS-V5 as the first-in-class dual HDAC-proteasome ligand. The inhibition of both targets was confirmed by biochemical and cellular assays as well as X-ray crystal structures of the 20S proteasome and HDAC6 complexed with RTS-V5. Cytotoxicity assays with leukemia and multiple myeloma cell lines as well as therapy refractory primary patient-derived leukemia cells demonstrated that RTS-V5 possesses potent and selective anticancer activity. Our results will thus guide the structure-based optimization of dual HDAC-proteasome inhibitors for the treatment of hematological malignancies. PubMed: 30365892DOI: 10.1021/acs.jmedchem.8b01487 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.5 Å) |
Structure validation
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