5L5R: Yeast 20s Proteasome With Human Beta5i (1-138;v31m) And Human Beta6 (97-111; 118-133)

Citation:
Abstract
Inhibition of the immunoproteasome subunit beta5i 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 alpha' beta' epoxyketone inhibitors with varying N-caps and P3-stereochemistry for mouse/human beta5c/beta5i 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 beta5c, human beta5i or mouse beta5i and the neighboring beta6 subunit. The structural data reveal exceptional conformations for the most selective human beta5i 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 beta5i inhibitors with potential clinical applications.
PDB ID: 5L5RDownload
MMDB ID: 144790
PDB Deposition Date: 2016/5/28
Updated in MMDB: 2016/12
Experimental Method:
x-ray diffraction
Resolution: 2.9  Å
Source Organism:
Saccharomyces cerevisiae S288C
Similar Structures:
Biological Unit for 5L5R: 28-meric; determined by author
Molecular Components in 5L5R
Label Count Molecule
Proteins (28 molecules)
2
Proteasome Subunit Alpha Type-2(Gene symbol: PRE8)
Molecule annotation
2
Proteasome Subunit Alpha Type-3(Gene symbol: PRE9)
Molecule annotation
2
Proteasome Subunit Alpha Type-4(Gene symbol: PRE6)
Molecule annotation
2
Proteasome Subunit Alpha Type-5(Gene symbol: PUP2)
Molecule annotation
2
Proteasome Subunit Alpha Type-6(Gene symbol: PRE5)
Molecule annotation
2
Probable Proteasome Subunit Alpha Type-7(Gene symbol: PRE10)
Molecule annotation
2
Proteasome Subunit Alpha Type-1(Gene symbol: SCL1)
Molecule annotation
2
Proteasome Subunit Beta Type-2(Gene symbol: PUP1)
Molecule annotation
2
Proteasome Subunit Beta Type-3(Gene symbol: PUP3)
Molecule annotation
2
Proteasome Subunit Beta Type-4(Gene symbol: PRE1)
Molecule annotation
2
Proteasome Subunit Beta Type-8,proteasome Subunit Beta Type-5
Molecule annotation
2
Proteasome Subunit Beta Type-6,proteasome Subunit Beta Type-1,proteasome Subunit Beta Type-6,proteasome Subunit Beta Type-1, Proteasome Subunit Beta Type-6
Molecule annotation
2
Proteasome Subunit Beta Type-7(Gene symbol: PRE4)
Molecule annotation
2
Proteasome Subunit Beta Type-1(Gene symbol: PRE3)
Molecule annotation
Chemicals (10 molecules)
1
8
2
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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