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- PDB-9gmt: Mtb PNPase Rv2783c Mutant L328F -

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Basic information

Entry
Database: PDB / ID: 9gmt
TitleMtb PNPase Rv2783c Mutant L328F
Components
  • Polyribonucleotide nucleotidyltransferase
  • RNA (5'-R(P*AP*AP*AP*AP*AP*AP*AP*AP*AP*AP*AP*AP*AP*AP*A)-3')
KeywordsRNA / PNPase / GpsI / RNA Degradosome / PNPase Inhibitor
Function / homology
Function and homology information


polyribonucleotide nucleotidyltransferase / polyribonucleotide nucleotidyltransferase activity / RNA catabolic process / mRNA catabolic process / RNA processing / peptidoglycan-based cell wall / 3'-5'-RNA exonuclease activity / magnesium ion binding / RNA binding / plasma membrane / cytosol
Similarity search - Function
Guanosine pentaphosphate synthetase I/polyribonucleotide nucleotidyltransferase / Polyribonucleotide nucleotidyltransferase, RNA-binding domain superfamily / Polyribonucleotide nucleotidyltransferase / Polyribonucleotide nucleotidyltransferase, RNA-binding domain / Polyribonucleotide nucleotidyltransferase, RNA binding domain / Exoribonuclease, phosphorolytic domain 1 / PNPase/RNase PH domain superfamily / Exoribonuclease, PH domain 2 superfamily / 3' exoribonuclease family, domain 1 / KH domain ...Guanosine pentaphosphate synthetase I/polyribonucleotide nucleotidyltransferase / Polyribonucleotide nucleotidyltransferase, RNA-binding domain superfamily / Polyribonucleotide nucleotidyltransferase / Polyribonucleotide nucleotidyltransferase, RNA-binding domain / Polyribonucleotide nucleotidyltransferase, RNA binding domain / Exoribonuclease, phosphorolytic domain 1 / PNPase/RNase PH domain superfamily / Exoribonuclease, PH domain 2 superfamily / 3' exoribonuclease family, domain 1 / KH domain / K Homology domain, type 1 / Type-1 KH domain profile. / K Homology domain, type 1 superfamily / S1 domain profile. / Ribosomal protein S1-like RNA-binding domain / S1 RNA binding domain / S1 domain / K Homology domain / K homology RNA-binding domain / Ribosomal protein S5 domain 2-type fold / Nucleic acid-binding, OB-fold
Similarity search - Domain/homology
: / RNA / RNA (> 10) / Polyribonucleotide nucleotidyltransferase
Similarity search - Component
Biological speciesMycobacterium tuberculosis (bacteria)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 1.93 Å
AuthorsGriesser, T. / Sander, P.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Swiss National Science Foundation310030_197699/1 Switzerland
CitationJournal: Nucleic Acids Res / Year: 2025
Title: Selective inhibition of Mycobacterium tuberculosis GpsI unveils a novel strategy to target the RNA metabolism.
Authors: Tizian Griesser / Rui Wang / Irene Pachon Angona / Janis Rogenmoser / Julia Obrist / Gisbert Schneider / Peter Sander /
Abstract: Polyribonucleotide nucleotidyl-transferases (PNPases) play a critical role in the degradation of mRNA. The mycobacterial PNPase, guanosine penta-phosphate synthase I (GpsI), is an essential enzyme ...Polyribonucleotide nucleotidyl-transferases (PNPases) play a critical role in the degradation of mRNA. The mycobacterial PNPase, guanosine penta-phosphate synthase I (GpsI), is an essential enzyme in Mycobacterium tuberculosis (Mtb), collaborating with endoribonucleases and helicases to process RNA. In this study, we identify GpsI as a novel and underexplored drug target. The inhibitor 1-(4'-(2-phenyl-5-(trifluoromethyl) oxazole-4-carboxamido)-[1,1'-biphenyl]-4-caroxamido) cyclopentane-1-carboxylic acid (X1), discovered through a whole-cell screening, specifically inhibits GpsI activity in biochemical assays. Biochemical and physiological analyses of engineered GpsI variants and recombinant Mycobacterium smegmatis pinpoint amino acids 328 and 527 as critical residues for the selective activity of X1 against Mtb complex. High-resolution cryo-electron microscopy analysis of the ternary GpsI-X1-poly(A) complex elucidates the drug-binding pocket, providing insight into its mechanism of action. This study introduces a potent inhibitor targeting the underexplored Mtb-GpsI and offers a molecular explanation for its selective specificity.
History
DepositionAug 29, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 25, 2025Provider: repository / Type: Initial release
Revision 1.0Jun 25, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jun 25, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jun 25, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Jun 25, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jun 25, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jul 9, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Polyribonucleotide nucleotidyltransferase
B: Polyribonucleotide nucleotidyltransferase
C: Polyribonucleotide nucleotidyltransferase
E: RNA (5'-R(P*AP*AP*AP*AP*AP*AP*AP*AP*AP*AP*AP*AP*AP*AP*A)-3')
hetero molecules


Theoretical massNumber of molelcules
Total (without water)196,9097
Polymers195,2184
Non-polymers1,6913
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, C1
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Polyribonucleotide nucleotidyltransferase / Polynucleotide phosphorylase / PNPase


Mass: 63441.617 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Details: Mutant L328F / Source: (gene. exp.) Mycobacterium tuberculosis (bacteria) / Gene: pnp, Rv2783c / Production host: Escherichia coli (E. coli)
References: UniProt: P9WI57, polyribonucleotide nucleotidyltransferase
#2: RNA chain RNA (5'-R(P*AP*AP*AP*AP*AP*AP*AP*AP*AP*AP*AP*AP*AP*AP*A)-3')


Mass: 4893.130 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Mycobacterium tuberculosis (bacteria)
#3: Chemical ChemComp-A1IM2 / 1-[[4-[4-[[2-phenyl-5-(trifluoromethyl)-1,3-oxazol-4-yl]carbonylamino]phenyl]phenyl]carbonylamino]cyclopentane-1-carboxylic acid / 1-(4'-(2-phenyl-5-(trifluoromethyl)oxazole-4-carboxamido)-[1,1'-biphenyl]-4-carboxamido)cyclopentane-1-carboxylic acid


Mass: 563.524 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C30H24F3N3O5 / Feature type: SUBJECT OF INVESTIGATION
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

Component
IDNameTypeDetailsEntity IDParent-IDSource
1gpsI Mycobacterium tuberculosis polynucleotide phosphorylaseCOMPLEXMycobacterium tuberculosis polynucleotide phosphorylase#1-#20MULTIPLE SOURCES
2Polyribonucleotide nucleotidyltransferaseCOMPLEX#11RECOMBINANT
3RNACOMPLEX#21RECOMBINANT
Molecular weightValue: 0.119 kDa/nm / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Mycobacterium tuberculosis (bacteria)1773
33Mycobacterium tuberculosis (bacteria)1773
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Escherichia coli (E. coli)562
33synthetic construct (others)32630
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE / Humidity: 90 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm / Calibrated defocus min: 1500 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 6 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2EPU3image acquisition
4cryoSPARCCTF correction
10cryoSPARCinitial Euler assignment
11cryoSPARCfinal Euler assignment
12cryoSPARCclassification
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 1.93 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1264862 / Algorithm: BACK PROJECTION / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 54.14 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.004314020
ELECTRON MICROSCOPYf_angle_d0.70519119
ELECTRON MICROSCOPYf_chiral_restr0.04852227
ELECTRON MICROSCOPYf_plane_restr0.00492471
ELECTRON MICROSCOPYf_dihedral_angle_d6.00182108

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