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- PDB-7yk1: Structural basis of human PRPS2 filaments -

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Basic information

Entry
Database: PDB / ID: 7yk1
TitleStructural basis of human PRPS2 filaments
ComponentsRibose-phosphate pyrophosphokinase 2
KeywordsTRANSFERASE / phosphoribosylpyrophosphate synthetase / complex / filament
Function / homology
Function and homology information


AMP biosynthetic process / 5-Phosphoribose 1-diphosphate biosynthesis / ribose phosphate diphosphokinase complex / ribose-phosphate diphosphokinase / ribose phosphate diphosphokinase activity / 5-phosphoribose 1-diphosphate biosynthetic process / pentose-phosphate shunt / purine nucleotide biosynthetic process / nucleobase-containing compound metabolic process / AMP binding ...AMP biosynthetic process / 5-Phosphoribose 1-diphosphate biosynthesis / ribose phosphate diphosphokinase complex / ribose-phosphate diphosphokinase / ribose phosphate diphosphokinase activity / 5-phosphoribose 1-diphosphate biosynthetic process / pentose-phosphate shunt / purine nucleotide biosynthetic process / nucleobase-containing compound metabolic process / AMP binding / animal organ regeneration / ADP binding / GDP binding / kinase activity / carbohydrate binding / phosphorylation / 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 / N-terminal domain of ribose phosphate pyrophosphokinase / Phosphoribosyl synthetase-associated domain / Ribose-phosphate pyrophosphokinase / Ribose-phosphate pyrophosphokinase, N-terminal domain / N-terminal domain of ribose phosphate pyrophosphokinase / Phosphoribosyltransferase-like / Phosphoribosyltransferase domain
Similarity search - Domain/homology
ADENOSINE-5'-DIPHOSPHATE / PHOSPHATE ION / Ribose-phosphate pyrophosphokinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.08 Å
AuthorsLu, G.M. / Hu, H.H. / Liu, J.L.
Funding support China, 2items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)No. 2021YFA0804700 China
National Natural Science Foundation of China (NSFC)No. 31771490 China
CitationJournal: Cell Biosci / Year: 2023
Title: Structural basis of human PRPS2 filaments.
Authors: Guang-Ming Lu / Huan-Huan Hu / Chia-Chun Chang / Jiale Zhong / Xian Zhou / Chen-Jun Guo / Tianyi Zhang / Yi-Lan Li / Boqi Yin / Ji-Long Liu /
Abstract: BACKGROUND: PRPP synthase (PRPS) transfers the pyrophosphate groups from ATP to ribose-5-phosphate to produce 5-phosphate ribose-1-pyrophosphate (PRPP), a key intermediate in the biosynthesis of ...BACKGROUND: PRPP synthase (PRPS) transfers the pyrophosphate groups from ATP to ribose-5-phosphate to produce 5-phosphate ribose-1-pyrophosphate (PRPP), a key intermediate in the biosynthesis of several metabolites including nucleotides, dinucleotides and some amino acids. There are three PRPS isoforms encoded in human genome. While human PRPS1 (hPRPS1) and human PRPS2 (hPRPS2) are expressed in most tissues, human PRPS3 (hPRPS3) is exclusively expressed in testis. Although hPRPS1 and hPRPS2 share 95% sequence identity, hPRPS2 has been shown to be less sensitive to allosteric inhibition and specifically upregulated in certain cancers in the translational level. Recent studies demonstrate that PRPS can form a subcellular compartment termed the cytoophidium in multiple organisms across prokaryotes and eukaryotes. Forming filaments and cytoophidia is considered as a distinctive mechanism involving the polymerization of the protein. Previously we solved the filament structures of Escherichia coli PRPS (ecPRPS) using cryo-electron microscopy (cryo-EM) .
RESULTS: Order to investigate the function and molecular mechanism of hPRPS2 polymerization, here we solve the polymer structure of hPRPS2 at 3.08 Å resolution. hPRPS2 hexamers stack into polymers ...RESULTS: Order to investigate the function and molecular mechanism of hPRPS2 polymerization, here we solve the polymer structure of hPRPS2 at 3.08 Å resolution. hPRPS2 hexamers stack into polymers in the conditions with the allosteric/competitive inhibitor ADP. The binding modes of ADP at the canonical allosteric site and at the catalytic active site are clearly determined. A point mutation disrupting the inter-hexamer interaction prevents hPRPS2 polymerization and results in significantly reduced catalytic activity.
CONCLUSION: Findings suggest that the regulation of hPRPS2 polymer is distinct from ecPRPS polymer and provide new insights to the regulation of hPRPS2 with structural basis.
History
DepositionJul 21, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 2, 2023Provider: repository / Type: Initial release
Revision 1.1Sep 20, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Ribose-phosphate pyrophosphokinase 2
B: Ribose-phosphate pyrophosphokinase 2
C: Ribose-phosphate pyrophosphokinase 2
D: Ribose-phosphate pyrophosphokinase 2
E: Ribose-phosphate pyrophosphokinase 2
F: Ribose-phosphate pyrophosphokinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)219,68830
Polymers213,8466
Non-polymers5,84224
Water00
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 2 / PPRibP / Phosphoribosyl pyrophosphate synthase II / PRS-II


Mass: 35640.969 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRPS2
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P11908, ribose-phosphate diphosphokinase
#2: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: PO4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: ADP, energy-carrying molecule*YM
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 structure of human phosphoribosylpyrophosphate synthetase2.
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaCl1
22 mMADP1
310 mMMagnesium chlorideMgCl21
425 mMTrimethylol aminomethane hydrochlorideTris-HCl1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid type: UltrAuFoil R1.2/1.3
VitrificationCryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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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 magnification: 22500 X / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN
Image recordingAverage exposure time: 4 sec. / Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 2403

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Processing

Software
NameVersionClassificationNB
phenix.real_space_refine1.20.1_4487refinement
PHENIX1.20.1_4487refinement
EM softwareName: RELION / Version: 3.1_beta / Category: particle selection
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 681672
3D reconstructionResolution: 3.08 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 140303 / Algorithm: FOURIER SPACE / Num. of class averages: 1 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 18.23 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.005314580
ELECTRON MICROSCOPYf_angle_d0.678119806
ELECTRON MICROSCOPYf_chiral_restr0.04712352
ELECTRON MICROSCOPYf_plane_restr0.00352472
ELECTRON MICROSCOPYf_dihedral_angle_d13.01392064

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