9CEE

20S Proteasome core particle beta-T1A mutant auto-inhibited state (Frame 1)

Summary for 9CEE

• Entry DOI: 10.2210/pdb9cee/pdb
• Related: 9CE5 9CE7 9CE8 9CEB
• EMDB information: 45494 45495 45496 45498 45499
• Descriptor: Proteasome subunit alpha, Proteasome subunit beta (2 entities in total)
• Functional Keywords: proteasome, proteolysis, antimicrobial protein
• Biological source: Mycobacterium tuberculosis; More
• Total number of polymer chains: 28
• Total formula weight: 718569.54

Authors

Zeytuni, N.,Uday, A.B.,Vahidi, S.,Turner, M. (deposition date: 2024-06-26, release date: 2025-03-12, Last modification date: 2025-04-16)

Primary citation

Turner, M.,Uday, A.B.,Velyvis, A.,Rennella, E.,Zeytuni, N.,Vahidi, S.
Structural basis for allosteric modulation of M. tuberculosis proteasome core particle.
Nat Commun, 16:3138-3138, 2025

PubMed Abstract: The Mycobacterium tuberculosis (Mtb) proteasome system selectively degrades damaged or misfolded proteins and is crucial for the pathogen's survival within the host. Targeting the 20S core particle (CP) offers a viable strategy for developing tuberculosis treatments. The activity of Mtb 20S CP, like that of its eukaryotic counterpart, is allosterically regulated, yet the specific conformations involved have not been captured in high-resolution structures to date. Here, we use single-particle electron cryomicroscopy and H/D exchange mass spectrometry to determine the Mtb 20S CP structure in an auto-inhibited state that is distinguished from the canonical resting state by the conformation of switch helices at the α/β interface. The rearrangement of these helices collapses the S1 pocket, effectively inhibiting substrate binding. Biochemical experiments show that the Mtb 20S CP activity can be altered through allosteric sites far from the active site. Our findings underscore the potential of targeting allostery to develop antituberculosis therapeutics.

PubMed: 40169579
DOI: 10.1038/s41467-025-58430-0

Experimental method

ELECTRON MICROSCOPY (2.89 Å)