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- PDB-7rlu: Structure of ALDH1L1 (10-formyltetrahydrofolate dehydrogenase) in... -

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Basic information

Entry
Database: PDB / ID: 7rlu
TitleStructure of ALDH1L1 (10-formyltetrahydrofolate dehydrogenase) in complex with NADP
ComponentsCytosolic 10-formyltetrahydrofolate dehydrogenase
KeywordsCYTOSOLIC PROTEIN / folate metabolism / acyl carrier protein / peptidyl carrier protein
Function / homology
Function and homology information


Metabolism of folate and pterines / aldehyde dehydrogenase (NADP+) activity / formyltetrahydrofolate dehydrogenase / formyltetrahydrofolate dehydrogenase activity / 10-formyltetrahydrofolate catabolic process / aldehyde dehydrogenase [NAD(P)+] activity / NADPH regeneration / aldehyde dehydrogenase (NAD+) activity / folic acid metabolic process / tetrahydrofolate biosynthetic process ...Metabolism of folate and pterines / aldehyde dehydrogenase (NADP+) activity / formyltetrahydrofolate dehydrogenase / formyltetrahydrofolate dehydrogenase activity / 10-formyltetrahydrofolate catabolic process / aldehyde dehydrogenase [NAD(P)+] activity / NADPH regeneration / aldehyde dehydrogenase (NAD+) activity / folic acid metabolic process / tetrahydrofolate biosynthetic process / one-carbon metabolic process / protein-containing complex binding / protein-containing complex / cytosol
Similarity search - Function
10-formyltetrahydrofolate dehydrogenase / Formyl transferase, C-terminal domain superfamily / Formyl transferase, C-terminal / Formyl transferase, C-terminal domain / Formyl transferase-like, C-terminal domain superfamily / Phosphoribosylglycinamide formyltransferase, active site / Phosphoribosylglycinamide formyltransferase active site. / Formyl transferase, N-terminal / Formyl transferase / Formyl transferase, N-terminal domain superfamily ...10-formyltetrahydrofolate dehydrogenase / Formyl transferase, C-terminal domain superfamily / Formyl transferase, C-terminal / Formyl transferase, C-terminal domain / Formyl transferase-like, C-terminal domain superfamily / Phosphoribosylglycinamide formyltransferase, active site / Phosphoribosylglycinamide formyltransferase active site. / Formyl transferase, N-terminal / Formyl transferase / Formyl transferase, N-terminal domain superfamily / Aldehyde dehydrogenase, glutamic acid active site / Aldehyde dehydrogenases glutamic acid active site. / Aldehyde dehydrogenase, cysteine active site / Aldehyde dehydrogenases cysteine active site. / Aldehyde dehydrogenase domain / Aldehyde dehydrogenase family / Aldehyde dehydrogenase, C-terminal / Aldehyde dehydrogenase, N-terminal / Aldehyde/histidinol dehydrogenase / ACP-like superfamily / Carrier protein (CP) domain profile. / Phosphopantetheine binding ACP domain
Similarity search - Domain/homology
NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 4'-PHOSPHOPANTETHEINE / Cytosolic 10-formyltetrahydrofolate dehydrogenase
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsTsybovsky, Y. / Sereda, V. / Golczak, M. / Krupenko, N.I. / Krupenko, S.A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)DK54388 United States
CitationJournal: Commun Biol / Year: 2022
Title: Structure of putative tumor suppressor ALDH1L1.
Authors: Yaroslav Tsybovsky / Valentin Sereda / Marcin Golczak / Natalia I Krupenko / Sergey A Krupenko /
Abstract: Putative tumor suppressor ALDH1L1, the product of natural fusion of three unrelated genes, regulates folate metabolism by catalyzing NADP-dependent conversion of 10-formyltetrahydrofolate to ...Putative tumor suppressor ALDH1L1, the product of natural fusion of three unrelated genes, regulates folate metabolism by catalyzing NADP-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and CO. Cryo-EM structures of tetrameric rat ALDH1L1 revealed the architecture and functional domain interactions of this complex enzyme. Highly mobile N-terminal domains, which remove formyl from 10-formyltetrahydrofolate, undergo multiple transient inter-domain interactions. The C-terminal aldehyde dehydrogenase domains, which convert formyl to CO, form unusually large interfaces with the intermediate domains, homologs of acyl/peptidyl carrier proteins (A/PCPs), which transfer the formyl group between the catalytic domains. The 4'-phosphopantetheine arm of the intermediate domain is fully extended and reaches deep into the catalytic pocket of the C-terminal domain. Remarkably, the tetrameric state of ALDH1L1 is indispensable for catalysis because the intermediate domain transfers formyl between the catalytic domains of different protomers. These findings emphasize the versatility of A/PCPs in complex, highly dynamic enzymatic systems.
History
DepositionJul 26, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 12, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 2, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _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 / _citation_author.identifier_ORCID

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Structure visualization

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Assembly

Deposited unit
A: Cytosolic 10-formyltetrahydrofolate dehydrogenase
B: Cytosolic 10-formyltetrahydrofolate dehydrogenase
D: Cytosolic 10-formyltetrahydrofolate dehydrogenase
C: Cytosolic 10-formyltetrahydrofolate dehydrogenase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)400,23512
Polymers395,8284
Non-polymers4,4078
Water50428
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area31990 Å2
ΔGint-141 kcal/mol
Surface area78020 Å2

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Components

#1: Protein
Cytosolic 10-formyltetrahydrofolate dehydrogenase / 10-FTHFDH / FDH / Aldehyde dehydrogenase family 1 member L1 / FBP-CI


Mass: 98957.047 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Aldh1l1, Fthfd / Cell line (production host): High Five / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P28037, formyltetrahydrofolate dehydrogenase
#2: Chemical
ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE


Mass: 743.405 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#3: Chemical
ChemComp-PNS / 4'-PHOSPHOPANTETHEINE


Mass: 358.348 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C11H23N2O7PS / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 28 / 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: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: ALDH1L1 in complex with NADP / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.395 MDa / Experimental value: NO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7
SpecimenConc.: 0.4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 298 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
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: REFMAC / Version: 5.8.0222 / Classification: refinement
EM software
IDNameVersionCategory
7Cootmodel fitting
10RELION3final Euler assignment
12RELION33D reconstruction
13REFMACmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: D2 (2x2 fold dihedral)
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 202398 / Symmetry type: POINT
Atomic model buildingProtocol: BACKBONE TRACE
RefinementCor.coef. Fo:Fc: 0.738 / Highest resolution: 2.9 Å / SU B: 21.467 / SU ML: 0.379 / ESU R: 0.814
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.37344 --
obs0.37344 104509 100 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 15.535 Å2
Baniso -1Baniso -2Baniso -3
1-2.63 Å2-0.03 Å2-0 Å2
2---1.71 Å2-0.01 Å2
3----0.92 Å2
Refinement stepCycle: 1 / Total: 18119
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0050.01418431
ELECTRON MICROSCOPYr_bond_other_d0.0010.01717025
ELECTRON MICROSCOPYr_angle_refined_deg0.9011.66624967
ELECTRON MICROSCOPYr_angle_other_deg0.6011.64439752
ELECTRON MICROSCOPYr_dihedral_angle_1_deg4.84552324
ELECTRON MICROSCOPYr_dihedral_angle_2_deg28.60722.982872
ELECTRON MICROSCOPYr_dihedral_angle_3_deg12.579153151
ELECTRON MICROSCOPYr_dihedral_angle_4_deg12.021596
ELECTRON MICROSCOPYr_chiral_restr0.0330.22424
ELECTRON MICROSCOPYr_gen_planes_refined0.0020.0220620
ELECTRON MICROSCOPYr_gen_planes_other0.0010.023368
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it0.11.6129320
ELECTRON MICROSCOPYr_mcbond_other0.11.6129319
ELECTRON MICROSCOPYr_mcangle_it0.1912.41711636
ELECTRON MICROSCOPYr_mcangle_other0.1912.41711637
ELECTRON MICROSCOPYr_scbond_it0.0411.6169111
ELECTRON MICROSCOPYr_scbond_other0.0411.6169108
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other0.0932.42113329
ELECTRON MICROSCOPYr_long_range_B_refined0.46118.66919173
ELECTRON MICROSCOPYr_long_range_B_other0.46118.66919174
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 2.9→2.975 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.594 7719 -
obs--100 %

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