9FST
Yeast 20S proteasome with human beta1i (1-51) in complex with epoxyketone inhibitor LU-001i
This is a non-PDB format compatible entry.
Summary for 9FST
| Entry DOI | 10.2210/pdb9fst/pdb |
| Related | 5CZ4 |
| Descriptor | Proteasome subunit alpha type-2, Proteasome subunit beta type-4, Proteasome subunit beta type-5, ... (20 entities in total) |
| Functional Keywords | proteasome, mutant, human chimeric subunit, structure-based drug development, inhibitor, binding analysis, hydrolase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 28 |
| Total formula weight | 734428.36 |
| Authors | Maurits, E.,Huber, E.M.,Dekker, P.M.,Wang, X.,Heinemeyer, W.,Florea, B.I.,Groll, M.,Overkleeft, H.S. (deposition date: 2024-06-21, release date: 2024-07-17, Last modification date: 2026-01-21) |
| Primary citation | Dekker, P.M.,Huber, E.M.,Maurits, E.,Wang, X.,Heinemeyer, W.,Florea, B.I.,Groll, M.,Overkleeft, H.S. Structure-Based Design of Pan-Selective Peptide Epoxyketones for the Three Human Immunoproteasome Active Sites. J.Med.Chem., 2026 Cited by PubMed Abstract: The proteasome inhibitors bortezomib, carfilzomib, and ixazomib all act by inhibiting multiple active sites of both constitutive proteasomes and immunoproteasomes. These clinical anticancer drugs are effective, but also display side effects, and evidence is amassing that their toxicity arises from constitutive proteasome inhibition. In this work, we describe the structure-guided discovery of a new class of pan-immunoproteasome-selective inhibitors. We identified the peptide epoxyketone BocPip-Ser (), which targets all three human immunoproteasome active sites potently and with excellent selectivity over constitutive proteasome active sites (IC values for i-subunits ≤ 0.92 μM; IC ratio β1c/β1i: 13, β2c/β2i: 14, β5c/β5i: 18; Table 1 and Figure 3). We propose compound (BocPip-Ser), which is of a similar size and general properties as carfilzomib, as a lead compound for the development of improved drugs targeting hematological cancers, and possibly also autoimmune diseases, driven by immunoproteasome but not constitutive proteasome activities. PubMed: 41504611DOI: 10.1021/acs.jmedchem.5c02639 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.75 Å) |
Structure validation
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