9WCX

Cryo-EM structure of the Mycobacterium abscessus cytochrome bcc:aa3 supercomplex

Summary for 9WCX

• Entry DOI: 10.2210/pdb9wcx/pdb
• EMDB information: 65878
• Descriptor: Prokaryotic respiratory supercomplex associate factor 1, DUF5130 domain-containing protein, Cytochrome c oxidase polypeptide 4, ... (25 entities in total)
• Functional Keywords: apo structure of supercomplex, oxidoreductase
• Biological source: Mycobacteroides abscessus; More
• Total number of polymer chains: 24
• Total formula weight: 773412.65

Authors

Mathiyazakan, V.,Gruber, G. (deposition date: 2025-08-18, release date: 2026-07-01)

Primary citation

Mathiyazakan, V.,Tan, E.X.Y.,Moraski, G.,Basak, S.,Saw, W.G.,Pethe, K.,Gruber, G.
The Mycobacterium abscessus cytochrome bcc:aa 3 oxidase structure paves the way for an agent targeting subunit QcrB.
Nat Commun, 17:-, 2026

PubMed Abstract: The cytochrome bcc:aa oxidase is the target of telacebec, a clinically advanced drug developed for Mycobacterium tuberculosis. However, telacebec is inactive against Mycobacterium abscessus, an opportunistic pathogen increasingly linked to chronic pulmonary infections and notoriously known for intrinsic resistance to numerous antibiotics. Here, we report the 2.6 Å cryo-electron microscopy structure of the M. abscessus bcc:aa cytochrome oxidase supercomplex, revealing key pathways and the evolution of the mycobacterial QcrB menaquinol-binding cavity. Structure-guided mutagenesis identified polymorphisms that modulate telacebec binding and potency in both M. abscessus and Mycobacterium smegmatis. Leveraging these insights, we designed ND-011458, a QcrB inhibitor with potent activity against M. abscessus and being bactericidal in combination with Clofazimine. The 2.26 Å inhibitor-bound structure elucidates its binding mode and provides a framework for the design of next-generation inhibitors for M. abscessus pulmonary diseases.

PubMed: 41932870
DOI: 10.1038/s41467-026-70805-5

Experimental method

ELECTRON MICROSCOPY (2.66 Å)