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- EMDB-80629: Tetrameric cystathionine beta-synthase of Mycobacterium tuberculo... -

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Basic information

Entry
Database: EMDB / ID: EMD-80629
TitleTetrameric cystathionine beta-synthase of Mycobacterium tuberculosis bound to O-Benzylhydroxylamine
Map dataSharpened Map
Sample
  • Complex: The ternary complex of O-Benzylhydroxylamine bound to MtbCBS
    • Protein or peptide: Probable cystathionine beta-synthase Rv1077
  • Ligand: O-benzylhydroxylamine
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: 3.43 Å
AuthorsPolepalli S / Roy A / 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_80629.png

Downloads & links

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Map

FileDownload / File: emd_80629.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: 0.258
Minimum - Maximum-1.5745627 - 2.2541249
Average (Standard dev.)0.00016406077 (±0.06125353)
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_80629_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_80629_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 O-Benzylhydroxylamine bound to MtbCBS

EntireName: The ternary complex of O-Benzylhydroxylamine bound to MtbCBS
Components
  • Complex: The ternary complex of O-Benzylhydroxylamine bound to MtbCBS
    • Protein or peptide: Probable cystathionine beta-synthase Rv1077
  • Ligand: O-benzylhydroxylamine

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

SupramoleculeName: The ternary complex of O-Benzylhydroxylamine 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: 50.512969 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MARIAQHISE LIGGTPLVRL NSVVPDGAGT VAAKVEYLNP GGSS(LLP)DRIAV KMIEAAEASG QLKPGGTIVE PTSGNT GVG LALVAQRRGY KCVFVCPDKV SEDKRNVLIA YGAEVVVCPT AVPPHDPASY YSVSDRLVRD IDGAWKPDQY ANPEGPA SH YVTTGPEIWA ...String:
MARIAQHISE LIGGTPLVRL NSVVPDGAGT VAAKVEYLNP GGSS(LLP)DRIAV KMIEAAEASG QLKPGGTIVE PTSGNT GVG LALVAQRRGY KCVFVCPDKV SEDKRNVLIA YGAEVVVCPT AVPPHDPASY YSVSDRLVRD IDGAWKPDQY ANPEGPA SH YVTTGPEIWA DTEGKVTHFV AGIGTGGTIT GAGRYLKEVS GGRVRIVGAD PEGSVYSGGA GRPYLVEGVG EDFWPAAY D PSVPDEIIAV SDSDSFDMTR RLAREEAMLV GGSCGMAVVA ALKVAEEAGP DALIVVLLPD GGRGYMSKIF NDAWMSSYG FLRSRLDGST EQSTVGDVLR RKSGALPALV HTHPSETVRD AIGILREYGV SQMPVVGAEP PVMAGEVAGS VSERELLSAV FEGRAKLAD AVSAHMSPPL RMIGAGELVS AAGKALRDWD ALMVVEEGKP VGVITRYDLL GFLSEGAGRR KLAAALEHHH H HH

UniProtKB: Probable cystathionine beta-synthase Rv1077

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Macromolecule #2: O-benzylhydroxylamine

MacromoleculeName: O-benzylhydroxylamine / type: ligand / ID: 2 / Number of copies: 4 / Formula: OBZ
Molecular weightTheoretical: 123.152 Da
Chemical component information

ChemComp-OBZ:
O-benzylhydroxylamine

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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: 45.0 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: 3.43 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 200810
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: ANGULAR RECONSTITUTION

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