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- PDB-8dbm: Human PRPS1 with Phosphate and PRPP; Filament Interface -

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Basic information

Entry
Database: PDB / ID: 8dbm
TitleHuman PRPS1 with Phosphate and PRPP; Filament Interface
ComponentsRibose-phosphate pyrophosphokinase 1
KeywordsTRANSFERASE / phosphoribosyl pyrophosphate synthetase / PRPP product
Function / homology
Function and homology information


5-Phosphoribose 1-diphosphate biosynthesis / hypoxanthine biosynthetic process / ribose phosphate diphosphokinase complex / ribonucleoside monophosphate biosynthetic process / ribose-phosphate diphosphokinase / ribose phosphate diphosphokinase activity / urate biosynthetic process / 5-phosphoribose 1-diphosphate biosynthetic process / pyrimidine nucleotide biosynthetic process / purine nucleotide biosynthetic process ...5-Phosphoribose 1-diphosphate biosynthesis / hypoxanthine biosynthetic process / ribose phosphate diphosphokinase complex / ribonucleoside monophosphate biosynthetic process / ribose-phosphate diphosphokinase / ribose phosphate diphosphokinase activity / urate biosynthetic process / 5-phosphoribose 1-diphosphate biosynthetic process / pyrimidine nucleotide biosynthetic process / purine nucleotide biosynthetic process / purine nucleobase metabolic process / kinase activity / nervous system development / magnesium ion binding / protein homodimerization activity / ATP binding / identical protein binding / cytoplasm / cytosol
Similarity search - Function
Phosphoribosyl pyrophosphate synthetase, conserved site / Phosphoribosyl pyrophosphate synthase signature. / Ribose-phosphate pyrophosphokinase, bacterial-type / Phosphoribosyl synthetase-associated domain / N-terminal domain of ribose phosphate pyrophosphokinase / Ribose-phosphate pyrophosphokinase / Ribose-phosphate pyrophosphokinase, N-terminal domain / N-terminal domain of ribose phosphate pyrophosphokinase / Phosphoribosyltransferase-like / Phosphoribosyltransferase domain
Similarity search - Domain/homology
PHOSPHATE ION / Chem-PRP / Ribose-phosphate pyrophosphokinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.4 Å
AuthorsHvorecny, K.L. / Kollman, J.M.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)F32AI145111 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM118396 United States
CitationJournal: Nat Struct Mol Biol / Year: 2023
Title: Human PRPS1 filaments stabilize allosteric sites to regulate activity.
Authors: Kelli L Hvorecny / Kenzee Hargett / Joel D Quispe / Justin M Kollman /
Abstract: The universally conserved enzyme phosphoribosyl pyrophosphate synthetase (PRPS) assembles filaments in evolutionarily diverse organisms. PRPS is a key regulator of nucleotide metabolism, and ...The universally conserved enzyme phosphoribosyl pyrophosphate synthetase (PRPS) assembles filaments in evolutionarily diverse organisms. PRPS is a key regulator of nucleotide metabolism, and mutations in the human enzyme PRPS1 lead to a spectrum of diseases. Here we determine structures of human PRPS1 filaments in active and inhibited states, with fixed assembly contacts accommodating both conformations. The conserved assembly interface stabilizes the binding site for the essential activator phosphate, increasing activity in the filament. Some disease mutations alter assembly, supporting the link between filament stability and activity. Structures of active PRPS1 filaments turning over substrate also reveal coupling of catalysis in one active site with product release in an adjacent site. PRPS1 filaments therefore provide an additional layer of allosteric control, conserved throughout evolution, with likely impact on metabolic homeostasis. Stabilization of allosteric binding sites by polymerization adds to the growing diversity of assembly-based enzyme regulatory mechanisms.
History
DepositionJun 14, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 15, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 22, 2023Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Mar 29, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Jun 12, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Ribose-phosphate pyrophosphokinase 1
B: Ribose-phosphate pyrophosphokinase 1
C: Ribose-phosphate pyrophosphokinase 1
D: Ribose-phosphate pyrophosphokinase 1
E: Ribose-phosphate pyrophosphokinase 1
F: Ribose-phosphate pyrophosphokinase 1
G: Ribose-phosphate pyrophosphokinase 1
H: Ribose-phosphate pyrophosphokinase 1
I: Ribose-phosphate pyrophosphokinase 1
J: Ribose-phosphate pyrophosphokinase 1
K: Ribose-phosphate pyrophosphokinase 1
L: Ribose-phosphate pyrophosphokinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)424,42560
Polymers418,02112
Non-polymers6,40448
Water43224
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Ribose-phosphate pyrophosphokinase 1 / PPRibP / Phosphoribosyl pyrophosphate synthase I / PRS-I


Mass: 34835.121 Da / Num. of mol.: 12
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRPS1 / Production host: Escherichia coli (E. coli)
References: UniProt: P60891, ribose-phosphate diphosphokinase
#2: Sugar
ChemComp-PRP / 1-O-pyrophosphono-5-O-phosphono-alpha-D-ribofuranose / ALPHA-PHOSPHORIBOSYLPYROPHOSPHORIC ACID / 1-O-pyrophosphono-5-O-phosphono-alpha-D-ribose / 1-O-pyrophosphono-5-O-phosphono-D-ribose / 1-O-pyrophosphono-5-O-phosphono-ribose


Type: D-saccharide / Mass: 390.070 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C5H13O14P3 / Feature type: SUBJECT OF INVESTIGATION
IdentifierTypeProgram
a-D-Ribf1PO35PO3IUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
#3: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: PO4 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical...
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 24 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 24 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

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

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Sample preparation

ComponentName: Filament interface of phosphoribosyl pyrophosphate synthetase 1 with phosphate and PRPP
Type: COMPLEX
Details: Six copies of PRPS1 assemble to form a hexamer; hexamers assembly linearly to form filaments.
Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.6
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid type: C-flat
VitrificationInstrument: HOMEMADE PLUNGER / Cryogen name: ETHANE

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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: 750 nm
Image recordingElectron dose: 90 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM software
IDNameVersionCategory
2Leginonimage acquisition
4CTFFIND4CTF correction
7Coot0.9.4.1model fitting
9cryoSPARC3initial Euler assignment
10RELION3.1final Euler assignment
12PHENIX1.183D reconstruction
13PHENIX1.18model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: D3 (2x3 fold dihedral)
3D reconstructionResolution: 2.4 Å / Resolution method: FSC 0.5 CUT-OFF / Num. of particles: 177611 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT

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