4QWL: Ycp Beta5-a50v Mutant In Complex With Carfilzomib

Citation:
Abstract
Inhibition of the 20S proteasome by bortezomib (Velcade) constitutes a successfully applied therapy for blood cancer. However, emerging resistance restricts its medicinal use. For example, mutations in the proteolytically active beta5-subunit of the proteasome, the main target of inhibitors, were reported to impair drug binding and thus to reduce therapeutic efficacy. Using yeast as a model system, we describe here a systematic evaluation of these mutations by cell growth analysis, proteasome inhibition assays, and X-ray crystallography. The 11 mutants examined display decreased proliferation rates, impaired proteolytic activity, and marked resistance to bortezomib as well as the alpha',beta'-epoxyketone inhibitors carfilzomib (Kyprolis) and ONX 0914, while the second-generation compound carfilzomib was the least affected. In total, 49 proteasome X-ray structures, including structural data on proteasome-carfilzomib complexes, reveal three distinct molecular mechanisms that hamper both drug binding and natural substrate turnover to an extent that is still compatible with cell survival.
PDB ID: 4QWLDownload
MMDB ID: 126683
PDB Deposition Date: 2014/7/16
Updated in MMDB: 2015/02
Experimental Method:
x-ray diffraction
Resolution: 2.6  Å
Source Organism:
Similar Structures:
Biological Unit for 4QWL: 28-meric; determined by author
Molecular Components in 4QWL
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-5(Gene symbol: PRE2)
Molecule annotation
2
Proteasome Subunit Beta Type-6(Gene symbol: PRE7)
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 (20 molecules)
1
8
2
4
3
6
4
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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