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- PDB-9q0o: Cryo-EM structure of PPAT-NUDT5 complex bound to 6-benzylthioinos... -

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Basic information

Entry
Database: PDB / ID: 9q0o
TitleCryo-EM structure of PPAT-NUDT5 complex bound to 6-benzylthioinosine-5'-monophosphate (6-benzylTIMP)
Components
  • ADP-sugar pyrophosphatase
  • Amidophosphoribosyltransferase
KeywordsBIOSYNTHETIC PROTEIN / Purine synthesis / phosphoribosyltransferase
Function / homology
Function and homology information


amidophosphoribosyltransferase / amidophosphoribosyltransferase activity / purine nucleobase biosynthetic process / ADP-D-ribose pyrophosphorylase / ribonucleoside diphosphate catabolic process / 8-oxo-dGDP phosphatase / ADP-sugar pyrophosphatase activity / ADP-ribose diphosphatase / nucleobase-containing small molecule metabolic process / ADP-ribose diphosphatase activity ...amidophosphoribosyltransferase / amidophosphoribosyltransferase activity / purine nucleobase biosynthetic process / ADP-D-ribose pyrophosphorylase / ribonucleoside diphosphate catabolic process / 8-oxo-dGDP phosphatase / ADP-sugar pyrophosphatase activity / ADP-ribose diphosphatase / nucleobase-containing small molecule metabolic process / ADP-ribose diphosphatase activity / D-ribose catabolic process / 'de novo' XMP biosynthetic process / Purine ribonucleoside monophosphate biosynthesis / 8-oxo-dGDP phosphatase activity / ribose phosphate metabolic process / 'de novo' AMP biosynthetic process / Phosphate bond hydrolysis by NUDT proteins / nucleotide metabolic process / ATP generation from poly-ADP-D-ribose / purine nucleotide biosynthetic process / GMP biosynthetic process / 'de novo' IMP biosynthetic process / nucleotidyltransferase activity / snoRNA binding / chromatin remodeling / magnesium ion binding / protein homodimerization activity / extracellular exosome / identical protein binding / nucleus / cytosol
Similarity search - Function
Amidophosphoribosyltransferase / Amidophosphoribosyltransferase, N-terminal / Glutamine amidotransferase domain / Glutamine amidotransferase type 2 domain profile. / Glutamine amidotransferase type 2 domain / Purine/pyrimidine phosphoribosyl transferases signature. / NUDIX hydrolase / Phosphoribosyl transferase domain / Phosphoribosyltransferase-like / Phosphoribosyltransferase domain ...Amidophosphoribosyltransferase / Amidophosphoribosyltransferase, N-terminal / Glutamine amidotransferase domain / Glutamine amidotransferase type 2 domain profile. / Glutamine amidotransferase type 2 domain / Purine/pyrimidine phosphoribosyl transferases signature. / NUDIX hydrolase / Phosphoribosyl transferase domain / Phosphoribosyltransferase-like / Phosphoribosyltransferase domain / NUDIX hydrolase, conserved site / Nudix box signature. / NUDIX domain / Nudix hydrolase domain profile. / NUDIX hydrolase domain / NUDIX hydrolase-like domain superfamily / Nucleophile aminohydrolases, N-terminal
Similarity search - Domain/homology
: / IRON/SULFUR CLUSTER / Amidophosphoribosyltransferase / ADP-sugar pyrophosphatase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsWitus, S.R.W. / Yang, Z. / Rape, M.
Funding support United States, 2items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
American Cancer SocietyPF-24-1257623-01-TBE United States
CitationJournal: Nature / Year: 2026
Title: Metabolite glues as a means of purine sensing and chemotherapeutic response.
Authors: Samuel R Witus / Megan M Kober / Heegwang Roh / Zhi Yang / Fouad Choueiry / Avani S Ghate / Denis V Titov / Michael Rapé /
Abstract: Molecular glues stabilize weak interactions to impart new functionalities to complexes. Although molecular glues have been described in plant signalling and as human therapeutics, it is unclear ...Molecular glues stabilize weak interactions to impart new functionalities to complexes. Although molecular glues have been described in plant signalling and as human therapeutics, it is unclear whether this modality provides endogenous regulation in human cells. Here we show that purine nucleotides are molecular glues that tether the rate-limiting enzyme in purine biosynthesis-phosphoribosyl pyrophosphate amidotransferase (PPAT)-to its inhibitor NUDT5. This mechanism allows cells to sense the levels of purines and to establish essential feedback control of their synthesis. We refer to such molecules as metabolite glues. Thiopurine chemotherapeutics, which have been in clinical use since the 1950s, glue the same complex but adopt distinct orientations for enhanced function. Unlike most known glues, the PPAT-NUDT5 metabolite-glue pocket can adjust its conformation to notable compound alterations, enabling increased glue potency and improved on-target activity. We therefore identify endogenous metabolite glues as a mode of nutrient sensing that can be exploited for therapeutic benefit.
History
DepositionAug 13, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 3, 2026Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Amidophosphoribosyltransferase
B: Amidophosphoribosyltransferase
C: Amidophosphoribosyltransferase
D: Amidophosphoribosyltransferase
E: ADP-sugar pyrophosphatase
F: ADP-sugar pyrophosphatase
G: ADP-sugar pyrophosphatase
H: ADP-sugar pyrophosphatase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)344,08016
Polymers340,8568
Non-polymers3,2248
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
Amidophosphoribosyltransferase / ATase / Glutamine phosphoribosylpyrophosphate amidotransferase / GPAT


Mass: 60690.281 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPAT, GPAT
Details (production host): pLVX-PPAT-V5-TwinStrep-IRES-puromycin
Cell line (production host): Expi293F / Production host: Homo sapiens (human) / References: UniProt: Q06203, amidophosphoribosyltransferase
#2: Protein
ADP-sugar pyrophosphatase / 8-oxo-dGDP phosphatase / Nuclear ATP-synthesis protein NUDIX5 / Nucleoside diphosphate-linked ...8-oxo-dGDP phosphatase / Nuclear ATP-synthesis protein NUDIX5 / Nucleoside diphosphate-linked moiety X motif 5 / Nudix motif 5 / hNUDT5 / YSA1H


Mass: 24523.686 Da / Num. of mol.: 4 / Mutation: Y74F
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NUDT5, NUDIX5, HSPC115 / Plasmid: pet28a / Details (production host): His-SUMO-TEV-NUDT5-Y74F / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): LOBSTR- -RIL
References: UniProt: Q9UKK9, ADP-ribose diphosphatase, 8-oxo-dGDP phosphatase, ADP-D-ribose pyrophosphorylase
#3: Chemical
ChemComp-SF4 / IRON/SULFUR CLUSTER


Mass: 351.640 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Fe4S4
#4: Chemical
ChemComp-A1CQ4 / 6-(benzylsulfanyl)-9-(5-O-phosphono-beta-D-ribofuranosyl)-9H-purine


Mass: 454.394 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H19N4O7PS / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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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
IDNameTypeEntity IDParent-IDSourceDetails (eV)
1Ternary complex of PPAT and NUDT5 with 6-benzylthioinosine-5'-monophosphateCOMPLEX#1-#20MULTIPLE SOURCES
2PPAT tetramerCOMPLEX#11RECOMBINANT1x PPAT tetramer per assembly
3NUDT5 dimerCOMPLEX#21RECOMBINANT2x NUDT5 dimers per assembly
Molecular weight
IDEntity assembly-IDValue (°)Experimental value
110.33 MDaNO
210.232 MDaNO
310.049 MDaNO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Homo sapiens (human)9606
22Homo sapiens (human)9606
33Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDStrainPlasmid
11Homo sapiens (human)9606
22Homo sapiens (human)9606Expi293FpLVX-PPAT-V5-TwinStrep-IRES-puromycin
33Escherichia coli (E. coli)562LOBSTR-BL21(DE3)-RILpet28a-His-SUMO-TEV-NUDT5-Y74F
Buffer solutionpH: 7.5
Details: 25 mM HEPES pH 7.5, 150 mM NaCl, 2 mM 6-benzylthioinosine-5'-monophosphate, 1 mM DTT
SpecimenConc.: 10 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 283 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / Alignment procedure: COMA FREE
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.3particle selection
2SerialEMimage acquisition
4cryoSPARC4.3CTF correction
7UCSF ChimeraXmodel fitting
9PHENIXmodel refinement
10Cootmodel refinement
11ISOLDEmodel refinement
12cryoSPARC4.3initial Euler assignment
13cryoSPARC4.3final Euler assignment
14cryoSPARC4.3classification
15cryoSPARC4.33D reconstruction
CTF correctionType: PHASE FLIPPING ONLY
SymmetryPoint symmetry: D2 (2x2 fold dihedral)
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 502672 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model buildingSource name: AlphaFold / Type: in silico model

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