5DKJ

Yeast 20S proteasome in complex with octreotide-PI

Summary for 5DKJ

• Entry DOI: 10.2210/pdb5dkj/pdb
• Related: 1RYP 2F16
• Descriptor: Proteasome subunit alpha type-2, Proteasome subunit beta type-4, Proteasome subunit beta type-5, ... (18 entities in total)
• Functional Keywords: hydrolase-hydrolase inhibitor complex, target delivery, proteasome, inhibitor, binding analysis, hydrolase/hydrolase inhibitor
• Biological source: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast); 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: 735007.85

Authors

Beck, P.,Cui, H.,Groll, M. (deposition date: 2015-09-03, release date: 2015-10-28, Last modification date: 2024-01-10)

Primary citation

Beck, P.,Cui, H.,Hegemann, J.D.,Marahiel, M.A.,Kruger, A.,Groll, M.
Targeted Delivery of Proteasome Inhibitors to Somatostatin-Receptor-Expressing Cancer Cells by Octreotide Conjugation.
Chemmedchem, 10:1969-1973, 2015

PubMed Abstract: Clinical application of proteasome inhibitors (PIs) is so far limited to peripheral blood cancers due to the pronounced cytotoxicity towards all cell types. Targeted delivery of PIs could permit the treatment of other cancers along with decreasing side effects. Herein we describe the first small-molecule proteasome inhibitor conjugate for targeted delivery, created by fusing PIs to a synthetic ligand of somatostatin receptors, which are highly expressed in a variety of tumors. X-ray crystallographic studies and in vitro IC50 measurements demonstrated that addition of the cyclopeptide octreotide as a targeting vehicle does not affect the PI's binding mode. The cytotoxicity of the conjugate against somatostatin-receptor-expressing cells was up to 11-fold higher than that of a non-targeting surrogate. We have therefore established PIs as a new payload for drug conjugates and have shown that targeted delivery thereof could be a promising approach for the broader application of this FDA-approved class of compounds.

PubMed: 26471124
DOI: 10.1002/cmdc.201500449

Experimental method

X-RAY DIFFRACTION (2.8 Å)