9wcx
Cryo-EM structure of the Mycobacterium abscessus cytochrome bcc:aa3 supercomplex
Structural highlights
FunctionB1MDZ6_MYCA9 Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Subunits 1-3 form the functional core of the enzyme complex. CO I is the catalytic subunit of the enzyme. Electrons originating in cytochrome c are transferred via the copper A center of subunit 2 and heme A of subunit 1 to the bimetallic center formed by heme A3 and copper B.[ARBA:ARBA00025218][RuleBase:RU363061] Publication Abstract from PubMedThe cytochrome bcc:aa(3) 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 A cryo-electron microscopy structure of the M. abscessus bcc:aa(3) 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 A inhibitor-bound structure elucidates its binding mode and provides a framework for the design of next-generation inhibitors for M. abscessus pulmonary diseases. The Mycobacterium abscessus cytochrome bcc:aa(3) oxidase structure paves the way for an agent targeting subunit QcrB.,Mathiyazakan V, Tan EXY, Moraski G, Basak S, Saw WG, Pethe K, Gruber G Nat Commun. 2026 Apr 3;17(1):4821. doi: 10.1038/s41467-026-70805-5. PMID:41932870[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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