5L5R
Yeast 20S proteasome with human beta5i (1-138;V31M) and human beta6 (97-111; 118-133)
Summary for 5L5R
| Entry DOI | 10.2210/pdb5l5r/pdb |
| Related | 5CZ4 |
| Descriptor | Proteasome subunit alpha type-2, Proteasome subunit beta type-4, Proteasome subunit beta type-8,Proteasome subunit beta type-5, ... (17 entities in total) |
| Functional Keywords | hydrolase complex, proteasome, mutant, binding analysis, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (Human) More |
| Cellular location | Cytoplasm: P23639 P22141 P30656 P23724 P30657 P38624 P23638 P40303 P32379 P40302 P21242 P21243 P25043 P25451 |
| Total number of polymer chains | 28 |
| Total formula weight | 731644.65 |
| Authors | Groll, M.,Huber, E.M. (deposition date: 2016-05-28, release date: 2016-11-09, Last modification date: 2024-01-10) |
| Primary citation | Huber, E.M.,Heinemeyer, W.,de Bruin, G.,Overkleeft, H.S.,Groll, M. A humanized yeast proteasome identifies unique binding modes of inhibitors for the immunosubunit beta 5i. EMBO J., 35:2602-2613, 2016 Cited by PubMed Abstract: Inhibition of the immunoproteasome subunit β5i alleviates autoimmune diseases in preclinical studies and represents a promising new anti-inflammatory therapy. However, the lack of structural data on the human immunoproteasome still hampers drug design. Here, we systematically determined the potency of seven α' β' epoxyketone inhibitors with varying N-caps and P3-stereochemistry for mouse/human β5c/β5i and found pronounced differences in their subunit and species selectivity. Using X-ray crystallography, the compounds were analyzed for their modes of binding to chimeric yeast proteasomes that incorporate key parts of human β5c, human β5i or mouse β5i and the neighboring β6 subunit. The structural data reveal exceptional conformations for the most selective human β5i inhibitors and highlight subtle structural differences as the major reason for the observed species selectivity. Altogether, the presented results validate the humanized yeast proteasome as a powerful tool for structure-based development of β5i inhibitors with potential clinical applications. PubMed: 27789522DOI: 10.15252/embj.201695222 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.9 Å) |
Structure validation
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