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- PDB-7a6s: Crystal Structure of Asn173Ser variant of Human Deoxyhypusine Synthase -

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Basic information

Entry
Database: PDB / ID: 7a6s
TitleCrystal Structure of Asn173Ser variant of Human Deoxyhypusine Synthase
ComponentsDeoxyhypusine synthase
KeywordsTRANSFERASE / deoxyhypusine synthase / hypusination / hypusine / translation / neurodegeneration / spermidine dhps deficiency
Function / homology
Function and homology information


deoxyhypusine synthase / peptidyl-lysine modification to peptidyl-hypusine / Hypusine synthesis from eIF5A-lysine / deoxyhypusine synthase activity / spermidine metabolic process / spermidine catabolic process / positive regulation of T cell proliferation / glucose homeostasis / translation / positive regulation of cell population proliferation ...deoxyhypusine synthase / peptidyl-lysine modification to peptidyl-hypusine / Hypusine synthesis from eIF5A-lysine / deoxyhypusine synthase activity / spermidine metabolic process / spermidine catabolic process / positive regulation of T cell proliferation / glucose homeostasis / translation / positive regulation of cell population proliferation / identical protein binding / cytosol / cytoplasm
Similarity search - Function
Deoxyhypusine synthase / Deoxyhypusine synthase superfamily / Deoxyhypusine synthase / DHS-like NAD/FAD-binding domain superfamily
Similarity search - Domain/homology
ACETATE ION / OXAMIC ACID / Deoxyhypusine synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.75 Å
AuthorsWator, E. / Wilk, P. / Grudnik, P.
Funding support Poland, 3items
OrganizationGrant numberCountry
Polish National Science CentreUMO-2019/33/B/NZ1/01839 Poland
Polish National Science CentreUMO-2019/35/N/NZ1/02805 Poland
Foundation for Polish ScienceTEAM TECH CORE FACILITY/2017-4/6 Poland
CitationJournal: Nat Commun / Year: 2023
Title: Cryo-EM structure of human eIF5A-DHS complex reveals the molecular basis of hypusination-associated neurodegenerative disorders.
Authors: Elżbieta Wątor / Piotr Wilk / Artur Biela / Michał Rawski / Krzysztof M Zak / Wieland Steinchen / Gert Bange / Sebastian Glatt / Przemysław Grudnik /
Abstract: Hypusination is a unique post-translational modification of the eukaryotic translation factor 5A (eIF5A) that is essential for overcoming ribosome stalling at polyproline sequence stretches. The ...Hypusination is a unique post-translational modification of the eukaryotic translation factor 5A (eIF5A) that is essential for overcoming ribosome stalling at polyproline sequence stretches. The initial step of hypusination, the formation of deoxyhypusine, is catalyzed by deoxyhypusine synthase (DHS), however, the molecular details of the DHS-mediated reaction remained elusive. Recently, patient-derived variants of DHS and eIF5A have been linked to rare neurodevelopmental disorders. Here, we present the cryo-EM structure of the human eIF5A-DHS complex at 2.8 Å resolution and a crystal structure of DHS trapped in the key reaction transition state. Furthermore, we show that disease-associated DHS variants influence the complex formation and hypusination efficiency. Hence, our work dissects the molecular details of the deoxyhypusine synthesis reaction and reveals how clinically-relevant mutations affect this crucial cellular process.
History
DepositionAug 26, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 23, 2022Provider: repository / Type: Initial release
Revision 1.1Apr 5, 2023Group: 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
Revision 1.2Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Deoxyhypusine synthase
B: Deoxyhypusine synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)82,67712
Polymers82,0352
Non-polymers64210
Water8,215456
1
A: Deoxyhypusine synthase
B: Deoxyhypusine synthase
hetero molecules

A: Deoxyhypusine synthase
B: Deoxyhypusine synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)165,35324
Polymers164,0704
Non-polymers1,28320
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555y,x,-z1
Buried area26860 Å2
ΔGint-92 kcal/mol
Surface area41810 Å2
MethodPISA
Unit cell
Length a, b, c (Å)105.382, 105.382, 159.902
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221
Components on special symmetry positions
IDModelComponents
11A-712-

HOH

21B-798-

HOH

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Components

#1: Protein Deoxyhypusine synthase / DHS


Mass: 41017.477 Da / Num. of mol.: 2 / Mutation: N173S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DHPS, DS / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: P49366, deoxyhypusine synthase
#2: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H3O2
#4: Chemical ChemComp-OXM / OXAMIC ACID


Mass: 89.050 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3NO3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 456 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.12 Å3/Da / Density % sol: 60.63 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.025-0.125 mM carboxylic acid mix, 30-60% precipitant mix (MPD, PEG 3350, PEG 1000), 100 mM Tris-Bicine pH = 8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 14, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.75→46.03 Å / Num. obs: 200356 / % possible obs: 99.9 % / Redundancy: 5.241 % / Biso Wilson estimate: 38.039 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.12 / Rrim(I) all: 0.133 / Χ2: 1.115 / Net I/σ(I): 7.2 / Num. measured all: 1050137
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
1.75-1.865.2852.3590.6317070332459322990.3852.61899.5
1.86-1.985.0781.1981.2315463230463304490.6511.337100
1.98-2.145.2240.6222.3914802128354283330.8690.69299.9
2.14-2.355.3720.3324.3214049526152261520.9590.368100
2.35-2.625.0490.1836.9911901423582235720.9810.205100
2.62-3.035.5240.11911.311502920827208240.9920.132100
3.03-3.75.1890.07817.159108017563175530.9940.08799.9
3.7-5.225.30.06723.247217513631136170.9940.07499.9
5.22-46.035.1590.06724.5538988757575570.9940.07599.8

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Processing

Software
NameVersionClassification
PHENIX1.17.1refinement
XDSdata reduction
XSCALEdata scaling
PDB_EXTRACT3.25data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6XXJ

6xxj


Resolution: 1.75→46.03 Å / SU ML: 0.29 / Cross valid method: THROUGHOUT / σ(F): 1.15 / Phase error: 24.86 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1989 2101 1.05 %
Rwork0.162 198145 -
obs0.1624 200246 99.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 263.09 Å2 / Biso mean: 50.8976 Å2 / Biso min: 22.35 Å2
Refinement stepCycle: final / Resolution: 1.75→46.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5230 0 92 455 5777
Biso mean--93.93 52.42 -
Num. residues----669
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 15

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.75-1.790.39931400.3788131391327999
1.79-1.830.35511410.33241314013281100
1.83-1.880.3411430.30971323413377100
1.88-1.940.33461400.2721315113291100
1.94-20.29131380.251325813396100
2-2.070.26451410.20951321013351100
2.07-2.160.19591420.18281325613398100
2.16-2.260.21331390.16511316713306100
2.26-2.370.21681400.15291321313353100
2.37-2.520.19311410.14081324813389100
2.52-2.720.18871390.14191320313342100
2.72-2.990.1781370.13711327613413100
2.99-3.420.16391400.13551322213362100
3.42-4.310.14881350.1291319813333100
4.31-46.030.20421450.1581323013375100

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