9S78

Yeast 20S Proteasome in Complex with Tellurophene-Tagged Carfilzomib

This is a non-PDB format compatible entry.

Summary for 9S78

• Entry DOI: 10.2210/pdb9s78/pdb
• Related: 4QW4
• Descriptor: Proteasome subunit alpha type-2, Proteasome subunit beta type-4, Proteasome subunit beta type-5, ... (19 entities in total)
• Functional Keywords: hydrolase-hydrolase inhibitor complex, proteasome, epoxyketone, natural product derivative, binding analysis, hydrolase
• Biological source: Saccharomyces cerevisiae (brewer's yeast); More
• Total number of polymer chains: 32
• Total formula weight: 735501.62

Authors

Potter, N.,Eddenden, A.,Fomina, A.,Dinesh, A.,Jackson, H.W.,McGuigan, A.,Groll, M.,Nitz, M. (deposition date: 2025-08-04, release date: 2025-12-24)

Primary citation

Potter, N.,Eddenden, A.,Fomina, A.,Dinesh, A.,Jackson, H.W.,McGuigan, A.P.,Groll, M.,Nitz, M.
Tellurophene-Tagged Carfilzomib Enables Single-Cell Mass Cytometric Mapping of Proteasome Activity.
Acs Chem.Biol., 2025

PubMed Abstract: Tracking small-molecule distribution in heterogeneous cell samples at single-cell resolution remains a major analytical challenge. Here, we present a tellurophene-functionalized analogue of the proteasome inhibitor Carfilzomib (TeCar) whose distribution can be followed by mass cytometric (MC) quantification while preserving target engagement and cytotoxicity. Structural and biochemical analyses confirm that TeCar binds the proteasome in a mode comparable to the clinically approved parent compound. Using MC, we demonstrate selective TeCar accumulation in malignant over immune cells within mixed populations, with cancer cells exhibiting 15 to 30-fold higher uptake. Tellurium signal correlates with proteasomal activity, and differential labeling among immune subsets reveals functional heterogeneity not captured by transcriptomics alone. These findings establish tellurophene tagging as a minimally perturbing and broadly applicable strategy for functional distribution studies at single-cell resolution.

PubMed: 41252648
DOI: 10.1021/acschembio.5c00691

Experimental method

X-RAY DIFFRACTION (3.15 Å)