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- PDB-9n9w: Cryo-EM structure of AMPPNP bound human phosphoribosylformylglyci... -

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Basic information

Entry
Database: PDB / ID: 9n9w
TitleCryo-EM structure of AMPPNP bound human phosphoribosylformylglycinamidine synthase
ComponentsPhosphoribosylformylglycinamidine synthase
KeywordsLIGASE / phosphoribosylformylglycinamidine synthase
Function / homology
Function and homology information


anterior head development / phosphoribosylformylglycinamidine synthase / phosphoribosylformylglycinamidine synthase activity / purine ribonucleoside monophosphate biosynthetic process / 'de novo' XMP biosynthetic process / Purine ribonucleoside monophosphate biosynthesis / 'de novo' AMP biosynthetic process / glutamine metabolic process / purine nucleotide biosynthetic process / GMP biosynthetic process ...anterior head development / phosphoribosylformylglycinamidine synthase / phosphoribosylformylglycinamidine synthase activity / purine ribonucleoside monophosphate biosynthetic process / 'de novo' XMP biosynthetic process / Purine ribonucleoside monophosphate biosynthesis / 'de novo' AMP biosynthetic process / glutamine metabolic process / purine nucleotide biosynthetic process / GMP biosynthetic process / 'de novo' IMP biosynthetic process / response to xenobiotic stimulus / extracellular exosome / ATP binding / metal ion binding / cytoplasm / cytosol
Similarity search - Function
Phosphoribosylformylglycinamidine synthase PurL / Phosphoribosylformylglycinamidine synthase, N-terminal / : / Formylglycinamide ribonucleotide amidotransferase N-terminal / FGAR-AT PurM_N-like domain / CobB/CobQ-like glutamine amidotransferase domain / CobB/CobQ-like glutamine amidotransferase domain / Phosphoribosylformylglycinamidine synthase, linker domain / Formylglycinamide ribonucleotide amidotransferase linker domain / Phosphoribosylformylglycinamidine synthase subunit PurS-like superfamily ...Phosphoribosylformylglycinamidine synthase PurL / Phosphoribosylformylglycinamidine synthase, N-terminal / : / Formylglycinamide ribonucleotide amidotransferase N-terminal / FGAR-AT PurM_N-like domain / CobB/CobQ-like glutamine amidotransferase domain / CobB/CobQ-like glutamine amidotransferase domain / Phosphoribosylformylglycinamidine synthase, linker domain / Formylglycinamide ribonucleotide amidotransferase linker domain / Phosphoribosylformylglycinamidine synthase subunit PurS-like superfamily / PurM-like, C-terminal domain / PurM-like, C-terminal domain superfamily / PurM-like, N-terminal domain superfamily / AIR synthase related protein, C-terminal domain / Glutamine amidotransferase type 1 domain profile. / Class I glutamine amidotransferase-like
Similarity search - Domain/homology
ADENOSINE-5'-DIPHOSPHATE / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / Phosphoribosylformylglycinamidine synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.31 Å
AuthorsSharma, N. / French, J.B.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM124898 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA299056 United States
CitationJournal: Nat Commun / Year: 2026
Title: Structural and molecular basis for allosteric regulation and catalytic coupling of human phosphoribosylformylglycinamidine synthase.
Authors: Nandini Sharma / Weijie Zhou / Jarrod B French /
Abstract: Purine nucleotides are ubiquitous molecules essential for all life. The de novo biosynthesis of purines is a metabolic dependency that is frequently reprogrammed in cancers and is a well-established ...Purine nucleotides are ubiquitous molecules essential for all life. The de novo biosynthesis of purines is a metabolic dependency that is frequently reprogrammed in cancers and is a well-established target for chemotherapies, immune modulation and antivirals. Here, we report cryo-electron microscopy structures of the multi-domain human phosphoribosylformylglycinamidine synthase, a central purine biosynthetic enzyme and foundational feature of the purinosome metabolon. These data capture, the proposed iminophosphate intermediate and provide the structural elucidation of an ammonia channel connecting the active sites of the glutaminase and synthase domains. Analysis of this series of structures and the accompanying biochemical data also reveal the molecular features and transient conformational changes that underlie allosteric regulation and catalytic coupling of the domains. This data resolves several longstanding mechanistic questions about this enzyme class and provides a strong foundation for therapeutic development.
History
DepositionFeb 11, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 25, 2026Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Phosphoribosylformylglycinamidine synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)149,5026
Polymers148,4961
Non-polymers1,0065
Water99155
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 Phosphoribosylformylglycinamidine synthase / FGAM synthase / FGAMS / Formylglycinamide ribonucleotide amidotransferase / FGAR amidotransferase / ...FGAM synthase / FGAMS / Formylglycinamide ribonucleotide amidotransferase / FGAR amidotransferase / FGAR-AT / Formylglycinamide ribotide amidotransferase / Phosphoribosylformylglycineamide amidotransferase


Mass: 148495.672 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PFAS, KIAA0361 / Production host: Homo sapiens (human)
References: UniProt: O15067, phosphoribosylformylglycinamidine synthase
#2: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
#3: Chemical ChemComp-ANP / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER


Mass: 506.196 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H17N6O12P3 / Comment: AMP-PNP, energy-carrying molecule analogue*YM
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 55 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
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: AMPPNP bound human phosphoribosylformylglycinamidine synthase
Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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 defocus max: 2500 nm / Nominal defocus min: 750 nm
Image recordingElectron dose: 45 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487 / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.31 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 366195 / Symmetry type: POINT
RefinementHighest resolution: 3.31 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0039709
ELECTRON MICROSCOPYf_angle_d0.60113286
ELECTRON MICROSCOPYf_dihedral_angle_d8.4231409
ELECTRON MICROSCOPYf_chiral_restr0.0411491
ELECTRON MICROSCOPYf_plane_restr0.0061746

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