4j70

From Proteopedia

(Difference between revisions)

Current revision

Yeast 20S proteasome in complex with the belactosin derivative 3e

Structural highlights

4j70 is a 20 chain structure with sequence from Saccharomyces cerevisiae. 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

PSA2_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.

Publication Abstract from PubMed

The natural product belactosin A (1) with a trans-cyclopropane structure is a useful prototype compound for developing potent proteasome (core particle, CP) inhibitors. To date, 1 and its analogs are the only CP ligands bind to both the non-primed S1 pocket as well as the primed substrate binding channel, however, these molecules harbor a high IC50 value of more than 1 microM. We have performed structure activity relationship studies, hereby elucidating unnatural cis-cyclopropane derivatives of 1 that exhibit high potency to primarily block the chymotrypsin-like active site of the human constitutive (cCP) and immunoproteasome (iCP). The most active compound 3e reversibly inhibits cCP and iCP similarly with an IC50 of 5.7 nM. X-ray crystallographic analysis of the yeast proteasome in complex with 3e revealed that the ligand accommodates predominantly to the primed substrate binding channel and covalently binds to the active site threonine residue via its beta-lactone ring-opening.

Potent Proteasome Inhibitors Derived from the Unnatural Cis-Cyclopropane Isomer of Belactosin A: Synthesis, Biological Activity, and Mode of Action.,Shuto S, Kawamura S, Unnno Y, List A, Sasaki T, Tanaka M, Arisawa M, Asai A, Groll M J Med Chem. 2013 Apr 2. PMID:23547757^[1]

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

References

↑ Shuto S, Kawamura S, Unnno Y, List A, Sasaki T, Tanaka M, Arisawa M, Asai A, Groll M. Potent Proteasome Inhibitors Derived from the Unnatural Cis-Cyclopropane Isomer of Belactosin A: Synthesis, Biological Activity, and Mode of Action. J Med Chem. 2013 Apr 2. PMID:23547757 doi:10.1021/jm4002296

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/4j70"

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 == Structural highlights ==
 <table><tr><td colspan='2'>[[4j70]] is a 20 chain structure with sequence from [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4J70 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4J70 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1KR:BENZYL+[(2S)-1-({(2R)-1-[(1S,2S)-2-{[(2R,3S,4S)-3-FORMYL-2-HYDROXY-4-METHYLHEXANOYL]AMINO}CYCLOPROPYL]-4-PHENYLBUTAN-2-YL}AMINO)-1-OXOPROPAN-2-YL]CARBAMATE'>1KR</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=1KR:BENZYL+[(2S)-1-({(2R)-1-[(1S,2S)-2-{[(2R,3S,4S)-3-FORMYL-2-HYDROXY-4-METHYLHEXANOYL]AMINO}CYCLOPROPYL]-4-PHENYLBUTAN-2-YL}AMINO)-1-OXOPROPAN-2-YL]CARBAMATE'>1KR</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=4j70 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4j70 OCA], [https://pdbe.org/4j70 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4j70 RCSB], [https://www.ebi.ac.uk/pdbsum/4j70 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4j70 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[https://www.uniprot.org/uniprot/PSA4_YEAST PSA4_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.
+[https://www.uniprot.org/uniprot/PSA2_YEAST PSA2_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.
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==

4j70

From Proteopedia

Current revision

Yeast 20S proteasome in complex with the belactosin derivative 3e

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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