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4qwk

From Proteopedia

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yCP beta5-A49T-A50V-double mutant in complex with carfilzomib

Structural highlights

4qwk is a 20 chain structure with sequence from Saccharomyces cerevisiae S288C. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.8Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PSB5_YEAST The proteasome degrades poly-ubiquitinated proteins in the cytoplasm and in the nucleus. It is essential for the regulated turnover of proteins and for the removal of misfolded proteins. The proteasome is a multicatalytic proteinase complex that is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. It has an ATP-dependent proteolytic activity. This unit is responsible of the chymotrypsin-like activity of the proteasome and is one of the principal target of the proteasome inhibitor bortezomib. This subunit is necessary for chymotryptic activity and degradation of ubiquitinated proteins.

Publication Abstract from PubMed

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.

Bortezomib-Resistant Mutant Proteasomes: Structural and Biochemical Evaluation with Carfilzomib and ONX 0914.,Huber EM, Heinemeyer W, Groll M Structure. 2015 Feb 3;23(2):407-17. doi: 10.1016/j.str.2014.11.019. Epub 2015 Jan, 15. PMID:25599643^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Huber EM, Heinemeyer W, Groll M. Bortezomib-Resistant Mutant Proteasomes: Structural and Biochemical Evaluation with Carfilzomib and ONX 0914. Structure. 2015 Feb 3;23(2):407-17. doi: 10.1016/j.str.2014.11.019. Epub 2015 Jan, 15. PMID:25599643 doi:http://dx.doi.org/10.1016/j.str.2014.11.019

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4qwk"

Categories: Large Structures | Saccharomyces cerevisiae S288C | Groll M | Heinemeyer W | Huber EM

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4qwk]] is a 20 chain structure with sequence from [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae_S288C Saccharomyces cerevisiae S288C]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QWK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4QWK FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3BV:N-{(2S)-2-[(MORPHOLIN-4-YLACETYL)AMINO]-4-PHENYLBUTANOYL}-L-LEUCYL-N-[(2R,3S,4S)-1,3-DIHYDROXY-2,6-DIMETHYLHEPTAN-4-YL]-L-PHENYLALANINAMIDE'>3BV</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.8&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3BV:N-{(2S)-2-[(MORPHOLIN-4-YLACETYL)AMINO]-4-PHENYLBUTANOYL}-L-LEUCYL-N-[(2R,3S,4S)-1,3-DIHYDROXY-2,6-DIMETHYLHEPTAN-4-YL]-L-PHENYLALANINAMIDE'>3BV</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4qwk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qwk OCA], [https://pdbe.org/4qwk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4qwk RCSB], [https://www.ebi.ac.uk/pdbsum/4qwk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4qwk ProSAT]</span></td></tr>
 </table>

4qwk

From Proteopedia

Current revision

yCP beta5-A49T-A50V-double mutant in complex with carfilzomib

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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