26GA

Tetrameric cystathionine beta-synthase of Mycobacterium tuberculosis bound to O-Benzylhydroxylamine

Replaces:  9U7N

Summary for 26GA

• Entry DOI: 10.2210/pdb26ga/pdb
• EMDB information: 80629
• Descriptor: Probable cystathionine beta-synthase Rv1077, O-benzylhydroxylamine (2 entities in total)
• Functional Keywords: inhibitor, lyase, complex
• Biological source: Mycobacterium tuberculosis H37Rv
• Total number of polymer chains: 4
• Total formula weight: 202544.48

Authors

Polepalli, S.,Roy, A.,Mondal, B.,Dutta, S. (deposition date: 2026-04-29, release date: 2026-09-09)

Primary citation

Polepalli, S.,Roy, A.,Mondal, B.,Singh, A.,Dutta, S.
Molecular insights into inhibitor action on the catalytic activity of Mycobacterium tuberculosis cystathionine beta-synthase enzyme.
Int.J.Biol.Macromol., 381:154013-154013, 2026

PubMed Abstract: Tuberculosis (TB) remains a major global health threat, with Mycobacterium tuberculosis (Mtb) infecting nearly a quarter of the global population. Drug-resistant TB and HIV-TB co-infections emphasize the need for novel therapeutic approaches targeting essential metabolic pathways. Here, we investigated Mtb cystathionine β-synthase (MtbCBS), a pyridoxal 5'-phosphate (PLP) dependent enzyme critical for sulfur metabolism and redox regulation, owing to its potential as a therapeutic target. Despite growing efforts to develop novel therapeutics, the widely used inhibitor aminooxy acetic acid (AOAA) is a non-specific inhibitor of all PLP-dependent enzymes, and the precise structural and mechanistic basis for its activity and specificity remains poorly understood. We present the high-resolution cryo-EM structure of full-length tetrameric MtbCBS in complex with AOAA, revealing a stable PLP-inhibitor adduct stabilized by two highly conserved active-site residues, T75 and Q147. This integrated approach employs cryo-EM, molecular dynamics (MD) simulations, Density Functional Theory (DFT) calculations, and comparative inhibition studies to reveal the molecular basis and determinants governing PLP-enzyme MtbCBS inhibition by AOAA. Through molecular mimic studies, we identified precise structural and electronic features of the inhibitor candidate that are critical for inhibition efficiency. These findings provide a mechanistic rationale for MtbCBS inhibition, and the unexplored roles of these key residues can be considered in the design of next-generation inhibitors targeting CBS enzymes implicated in infectious diseases, cancer, and neurological disorders.

PubMed: 42575362
DOI: 10.1016/j.ijbiomac.2026.154013

Experimental method

ELECTRON MICROSCOPY (3.43 Å)