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- PDB-8uv8: M. tuberculosis CTP synthase tetramer bound to CTP -

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Basic information

Entry
Database: PDB / ID: 8uv8
TitleM. tuberculosis CTP synthase tetramer bound to CTP
ComponentsCTP synthase
KeywordsLIGASE / metabolic enzyme
Function / homology
Function and homology information


cytoophidium / CTP synthase (glutamine hydrolysing) / CTP synthase activity / 'de novo' CTP biosynthetic process / pyrimidine nucleobase biosynthetic process / ATP binding / metal ion binding / identical protein binding / cytosol
Similarity search - Function
CTP synthase / CTP synthase, N-terminal / CTP synthase GATase domain / CTP synthase N-terminus / Glutamine amidotransferase / Glutamine amidotransferase class-I / Glutamine amidotransferase type 1 domain profile. / Class I glutamine amidotransferase-like / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
CYTIDINE-5'-TRIPHOSPHATE / CTP synthase
Similarity search - Component
Biological speciesMycobacterium tuberculosis (bacteria)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsLynch, E.M. / Kollman, J.M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35 GM149542 United States
CitationJournal: Nat Commun / Year: 2025
Title: Evolutionarily divergent Mycobacterium tuberculosis CTP synthase filaments are under selective pressure.
Authors: Eric M Lynch / Yao Lu / Jin Ho Park / Lin Shao / Justin M Kollman / E Hesper Rego /
Abstract: The final and rate-limiting enzyme in pyrimidine biosynthesis, cytidine triphosphate synthase (CTPS), is essential for the viability of Mycobacterium tuberculosis and other mycobacteria. Its product, ...The final and rate-limiting enzyme in pyrimidine biosynthesis, cytidine triphosphate synthase (CTPS), is essential for the viability of Mycobacterium tuberculosis and other mycobacteria. Its product, cytidine triphosphate (CTP), is critical for RNA, DNA, lipid and cell wall synthesis, and is involved in chromosome segregation. In various organisms across the tree of life, CTPS assembles into higher-order filaments, leading us to hypothesize that M. tuberculosis CTPS (mtCTPS) also forms higher-order structures. Here, we show that mtCTPS does assemble into filaments but with an unusual architecture not seen in other organisms. Through a combination of structural, biochemical, and cellular techniques, we show that polymerization stabilizes the active conformation of the enzyme and resists product inhibition, potentially allowing for the highly localized production of CTP within the cell. Indeed, CTPS filaments localize near the CTP-dependent complex needed for chromosome segregation, and cells expressing mutant enzymes unable to polymerize are altered in their ability to robustly form this complex. Intriguingly, mutants that inhibit filament formation are under positive selection in clinical isolates of M. tuberculosis, pointing to a critical role needed to withstand pressures imposed by the host and/or antibiotics. Taken together, our data reveal an unexpected mechanism for the spatially organized production of a critical nucleotide in M. tuberculosis, which may represent a vulnerability of the pathogen that can be exploited with chemotherapy.
History
DepositionNov 2, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 2, 2025Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: CTP synthase
B: CTP synthase
C: CTP synthase
D: CTP synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)262,13416
Polymers258,1714
Non-polymers3,96212
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein
CTP synthase


Mass: 64542.797 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis (bacteria) / Gene: pyrG / Production host: Escherichia coli (E. coli) / References: UniProt: A0A045H225
#2: Chemical
ChemComp-CTP / CYTIDINE-5'-TRIPHOSPHATE


Mass: 483.156 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C9H16N3O14P3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: CTP synthase tetramer / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Mycobacterium tuberculosis (bacteria)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 65 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM software
IDNameCategoryFitting-ID
2Leginonimage acquisition
4cryoSPARCCTF correction
7UCSF Chimeramodel fitting1
10ISOLDEmodel refinement1
12PHENIXmodel refinement2
13RELIONinitial Euler assignment
15RELIONfinal Euler assignment
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: D2 (2x2 fold dihedral)
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.5 CUT-OFF / Num. of particles: 31423 / Symmetry type: POINT
Atomic model building
IDProtocol
1FLEXIBLE FIT
2FLEXIBLE FIT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00517080
ELECTRON MICROSCOPYf_angle_d0.71923316
ELECTRON MICROSCOPYf_dihedral_angle_d12.2476204
ELECTRON MICROSCOPYf_chiral_restr0.0452636
ELECTRON MICROSCOPYf_plane_restr0.013036

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