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- EMDB-80619: Tetrameric cystathionine beta-synthase of Mycobacterium tuberculo... -

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Basic information

Entry
Database: EMDB / ID: EMD-80619
TitleTetrameric cystathionine beta-synthase of Mycobacterium tuberculosis bound to AOAA
Map dataSharpened Map
Sample
  • Complex: The ternary complex of AOAA-bound to MtbCBS
    • Protein or peptide: Probable cystathionine beta-synthase Rv1077
  • Ligand: 4'-DEOXY-4'-ACETYLYAMINO-PYRIDOXAL-5'-PHOSPHATE
KeywordsInhibitor / Lyase / Complex
Function / homology
Function and homology information


cystathionine beta-synthase / cystathionine beta-synthase activity / : / cysteine synthase activity / : / peptidoglycan-based cell wall / extracellular region / plasma membrane / cytoplasm
Similarity search - Function
Cystathionine beta-synthase, C-terminal domain / Cystathionine beta-synthase / : / Pyridoxal-phosphate dependent enzyme / Pyridoxal-phosphate dependent enzyme / Tryptophan synthase beta subunit-like PLP-dependent enzyme / Domain in cystathionine beta-synthase and other proteins. / CBS domain superfamily / CBS domain / CBS domain / CBS domain profile.
Similarity search - Domain/homology
Probable cystathionine beta-synthase Rv1077
Similarity search - Component
Biological speciesMycobacterium tuberculosis (strain ATCC 25618 / H37Rv) (bacteria) / Mycobacterium tuberculosis H37Rv (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.34 Å
AuthorsRoy A / Polepalli S / Mondal B / Dutta S
Funding support India, 2 items
OrganizationGrant numberCountry
Department of Biotechnology (DBT, India)(BT/INF/22/SP22844/2017) India
Department of Science & Technology (DST, India)(SR/FST/LSII-039/2015) India
CitationJournal: Int J Biol Macromol / Year: 2026
Title: Molecular insights into inhibitor action on the catalytic activity of Mycobacterium tuberculosis cystathionine β-synthase enzyme.
Authors: Sainath Polepalli / Anupam Roy / Bapan Mondal / Amit Singh / Somnath Dutta /
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 ...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.
History
DepositionApr 29, 2026-
Header (metadata) releaseSep 9, 2026-
Map releaseSep 9, 2026-
UpdateSep 9, 2026-
Current statusSep 9, 2026Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_80619.png

Downloads & links

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Map

FileDownload / File: emd_80619.map.gz / Format: CCP4 / Size: 95 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened Map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.92 Å/pix.
x 292 pix.
= 268.64 Å		0.92 Å/pix.
x 292 pix.
= 268.64 Å		0.92 Å/pix.
x 292 pix.
= 268.64 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.92 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.205
Minimum - Maximum-0.9877389 - 1.9866819
Average (Standard dev.)0.00016239483 (±0.04521833)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions292292292
Spacing292292292
CellA=B=C: 268.64 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map-B

Fileemd_80619_half_map_1.map
AnnotationHalf Map-B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map-A

Fileemd_80619_half_map_2.map
AnnotationHalf Map-A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : The ternary complex of AOAA-bound to MtbCBS

EntireName: The ternary complex of AOAA-bound to MtbCBS
Components
  • Complex: The ternary complex of AOAA-bound to MtbCBS
    • Protein or peptide: Probable cystathionine beta-synthase Rv1077
  • Ligand: 4'-DEOXY-4'-ACETYLYAMINO-PYRIDOXAL-5'-PHOSPHATE

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Supramolecule #1: The ternary complex of AOAA-bound to MtbCBS

SupramoleculeName: The ternary complex of AOAA-bound to MtbCBS / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) (bacteria)

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Macromolecule #1: Probable cystathionine beta-synthase Rv1077

MacromoleculeName: Probable cystathionine beta-synthase Rv1077 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO / EC number: cystathionine beta-synthase
Source (natural)Organism: Mycobacterium tuberculosis H37Rv (bacteria)
Molecular weightTheoretical: 50.284848 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MARIAQHISE LIGGTPLVRL NSVVPDGAGT VAAKVEYLNP GGSSKDRIAV KMIEAAEASG QLKPGGTIVE PTSGNTGVGL ALVAQRRGY KCVFVCPDKV SEDKRNVLIA YGAEVVVCPT AVPPHDPASY YSVSDRLVRD IDGAWKPDQY ANPEGPASHY V TTGPEIWA ...String:
MARIAQHISE LIGGTPLVRL NSVVPDGAGT VAAKVEYLNP GGSSKDRIAV KMIEAAEASG QLKPGGTIVE PTSGNTGVGL ALVAQRRGY KCVFVCPDKV SEDKRNVLIA YGAEVVVCPT AVPPHDPASY YSVSDRLVRD IDGAWKPDQY ANPEGPASHY V TTGPEIWA DTEGKVTHFV AGIGTGGTIT GAGRYLKEVS GGRVRIVGAD PEGSVYSGGA GRPYLVEGVG EDFWPAAYDP SV PDEIIAV SDSDSFDMTR RLAREEAMLV GGSCGMAVVA ALKVAEEAGP DALIVVLLPD GGRGYMSKIF NDAWMSSYGF LRS RLDGST EQSTVGDVLR RKSGALPALV HTHPSETVRD AIGILREYGV SQMPVVGAEP PVMAGEVAGS VSERELLSAV FEGR AKLAD AVSAHMSPPL RMIGAGELVS AAGKALRDWD ALMVVEEGKP VGVITRYDLL GFLSEGAGRR KLAAALEHHH HHH

UniProtKB: Probable cystathionine beta-synthase Rv1077

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Macromolecule #2: 4'-DEOXY-4'-ACETYLYAMINO-PYRIDOXAL-5'-PHOSPHATE

MacromoleculeName: 4'-DEOXY-4'-ACETYLYAMINO-PYRIDOXAL-5'-PHOSPHATE / type: ligand / ID: 2 / Number of copies: 4 / Formula: IK2
Molecular weightTheoretical: 322.208 Da
Chemical component information

ChemComp-IK2:
4'-DEOXY-4'-ACETYLYAMINO-PYRIDOXAL-5'-PHOSPHATE

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 44.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 5.0 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: D2 (2x2 fold dihedral) / Resolution.type: BY AUTHOR / Resolution: 3.34 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 89896
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: ANGULAR RECONSTITUTION

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