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- EMDB-49179: Cryo-EM structure of AMPPNP bound human phosphoribosylformylglyci... -

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Basic information

Entry
Database: EMDB / ID: EMD-49179
TitleCryo-EM structure of AMPPNP bound human phosphoribosylformylglycinamidine synthase
Map datastructure of AMPPNP bound human phosphoribosylformylglycinamidine synthase
Sample
  • Organelle or cellular component: AMPPNP bound human phosphoribosylformylglycinamidine synthase
    • Protein or peptide: Phosphoribosylformylglycinamidine synthase
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER
  • Ligand: MAGNESIUM ION
  • Ligand: water
Keywordsphosphoribosylformylglycinamidine synthase / LIGASE
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
Phosphoribosylformylglycinamidine synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.31 Å
AuthorsSharma N / French JB
Funding support United States, 2 items
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, 2025-
Header (metadata) releaseFeb 25, 2026-
Map releaseFeb 25, 2026-
UpdateFeb 25, 2026-
Current statusFeb 25, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_49179.png

Downloads & links

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Map

FileDownload / File: emd_49179.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationstructure of AMPPNP bound human phosphoribosylformylglycinamidine synthase
Projections & slices

Image control

Size
Brightness
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.65 Å/pix.
x 320 pix.
= 208.64 Å		0.65 Å/pix.
x 320 pix.
= 208.64 Å		0.65 Å/pix.
x 320 pix.
= 208.64 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.652 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.147
Minimum - Maximum-0.0017853085 - 2.1874287
Average (Standard dev.)0.0027841765 (±0.039837368)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 208.64 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Additional Map

Fileemd_49179_additional_1.map
AnnotationAdditional Map
Projections & Slices
AxesZYX

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Histogram

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Half map: Half Map B

Fileemd_49179_half_map_1.map
AnnotationHalf Map B
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: Half Map A

Fileemd_49179_half_map_2.map
AnnotationHalf Map A
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : AMPPNP bound human phosphoribosylformylglycinamidine synthase

EntireName: AMPPNP bound human phosphoribosylformylglycinamidine synthase
Components
  • Organelle or cellular component: AMPPNP bound human phosphoribosylformylglycinamidine synthase
    • Protein or peptide: Phosphoribosylformylglycinamidine synthase
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER
  • Ligand: MAGNESIUM ION
  • Ligand: water

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Supramolecule #1: AMPPNP bound human phosphoribosylformylglycinamidine synthase

SupramoleculeName: AMPPNP bound human phosphoribosylformylglycinamidine synthase
type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Phosphoribosylformylglycinamidine synthase

MacromoleculeName: Phosphoribosylformylglycinamidine synthase / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: phosphoribosylformylglycinamidine synthase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 148.495672 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSPVLHFYVR PSGHEGAAPG HTRRKLQGKL PELQGVETEL CYNVNWTAEA LPSAEETKKL MWLFGCPLLL DDVARESWLL PGSNDLLLE VGPRLNFSTP TSTNIVSVCR ATGLGPVDRV ETTRRYRLSF AHPPSAEVEA IALATLHDRM TEQHFPHPIQ S FSPESMPE ...String:
MSPVLHFYVR PSGHEGAAPG HTRRKLQGKL PELQGVETEL CYNVNWTAEA LPSAEETKKL MWLFGCPLLL DDVARESWLL PGSNDLLLE VGPRLNFSTP TSTNIVSVCR ATGLGPVDRV ETTRRYRLSF AHPPSAEVEA IALATLHDRM TEQHFPHPIQ S FSPESMPE PLNGPINILG EGRLALEKAN QELGLALDSW DLDFYTKRFQ ELQRNPSTVE AFDLAQSNSE HSRHWFFKGQ LH VDGQKLV HSLFESIMST QESSNPNNVL KFCDNSSAIQ GKEVRFLRPE DPTRPSRFQQ QQGLRHVVFT AETHNFPTGV CPF SGATTG TGGRIRDVQC TGRGAHVVAG TAGYCFGNLH IPGYNLPWED PSFQYPGNFA RPLEVAIEAS NGASDYGNKF GEPV LAGFA RSLGLQLPDG QRREWIKPIM FSGGIGSMEA DHISKEAPEP GMEVVKVGGP VYRIGVGGGA ASSVQVQGDN TSDLD FGAV QRGDPEMEQK MNRVIRACVE APKGNPICSL HDQGAGGNGN VLKELSDPAG AIIYTSRFQL GDPTLNALEI WGAEYQ ESN ALLLRSPNRD FLTHVSARER CPACFVGTIT GDRRIVLVDD RECPVRRNGQ GDAPPTPLPT PVDLELEWVL GKMPRKE FF LQRKPPMLQP LALPPGLSVH QALERVLRLP AVASKRYLTN KVDRSVGGLV AQQQCVGPLQ TPLADVAVVA LSHEELIG A ATALGEQPVK SLLDPKVAAR LAVAEALTNL VFALVTDLRD VKCSGNWMWA AKLPGEGAAL ADACEAMVAV MAALGVAVD GGKDSLSMAA RVGTETVRAP GSLVISAYAV CPDITATVTP DLKHPEGRGH LLYVALSPGQ HRLGGTALAQ CFSQLGEHPP DLDLPENLV RAFSITQGLL KDRLLCSGHD VSDGGLVTCL LEMAFAGNCG LQVDVPVPRV DVLSVLFAEE PGLVLEVQEP D LAQVLKRY RDAGLHCLEL GHTGEAGPHA MVRVSVNGAV VLEEPVGELR ALWEETSFQL DRLQAEPRCV AEEERGLRER MG PSYCLPP TFPKASVPRE PGGPSPRVAI LREEGSNGDR EMADAFHLAG FEVWDVTMQD LCSGAIGLDT FRGVAFVGGF SYA DVLGSA KGWAAAVTFH PRAGAELRRF RKRPDTFSLG VCNGCQLLAL LGWVGGDPNE DAAEMGPDSQ PARPGLLLRH NLSG RYESR WASVRVGPGP ALMLRGMEGA VLPVWSAHGE GYVAFSSPEL QAQIEARGLA PLHWADDDGN PTEQYPLNPN GSPGG VAGI CSCDGRHLAV MPHPERAVRP WQWAWRPPPF DTLTTSPWLQ LFINARNWTL EGSCTRTRPL EQKLISEEDL AANDIL DYK DDDDKV

UniProtKB: Phosphoribosylformylglycinamidine synthase

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Macromolecule #2: ADENOSINE-5'-DIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-DIPHOSPHATE / type: ligand / ID: 2 / Number of copies: 1 / Formula: ADP
Molecular weightTheoretical: 427.201 Da
Chemical component information

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

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Macromolecule #3: PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER

MacromoleculeName: PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / type: ligand / ID: 3 / Number of copies: 1 / Formula: ANP
Molecular weightTheoretical: 506.196 Da
Chemical component information

ChemComp-ANP:
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / AMP-PNP, energy-carrying molecule analogue*YM

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Macromolecule #4: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 4 / Number of copies: 3 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #5: water

MacromoleculeName: water / type: ligand / ID: 5 / Number of copies: 55 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 45.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.75 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.31 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 366195
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING
FSC plot (resolution estimation)

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