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- PDB-7a6t: Crystal Structure of Asn173Ser variant of Human Deoxyhypusine Syn... -

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Basic information

Entry
Database: PDB / ID: 7a6t
TitleCrystal Structure of Asn173Ser variant of Human Deoxyhypusine Synthase in complex with NAD and spermidine
ComponentsDeoxyhypusine synthase
KeywordsTRANSFERASE / deoxyhypusine synthase / hypusination / hypusine / translation / neurodegeneration / spermidine dhps deficiency
Function / homology
Function and homology information


deoxyhypusine synthase / Hypusine synthesis from eIF5A-lysine / peptidyl-lysine modification to peptidyl-hypusine / 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 / Hypusine synthesis from eIF5A-lysine / peptidyl-lysine modification to peptidyl-hypusine / 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 / cytoplasm / cytosol
Similarity search - Function
Deoxyhypusine synthase / Deoxyhypusine synthase superfamily / Deoxyhypusine synthase / DHS-like NAD/FAD-binding domain superfamily
Similarity search - Domain/homology
BETA-MERCAPTOETHANOL / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / OXAMIC ACID / SPERMIDINE / Deoxyhypusine synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.66 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)84,19214
Polymers82,0352
Non-polymers2,15712
Water6,846380
1
A: Deoxyhypusine synthase
B: Deoxyhypusine synthase
hetero molecules

A: Deoxyhypusine synthase
B: Deoxyhypusine synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)168,38428
Polymers164,0704
Non-polymers4,31424
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555y,x,-z1
Buried area32970 Å2
ΔGint-77 kcal/mol
Surface area39650 Å2
MethodPISA
Unit cell
Length a, b, c (Å)105.032, 105.032, 159.997
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
11B-1861-

HOH

21B-1870-

HOH

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Components

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Protein , 1 types, 2 molecules AB

#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

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Non-polymers , 6 types, 392 molecules

#2: Chemical ChemComp-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE


Mass: 663.425 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Comment: NAD*YM
#3: Chemical ChemComp-SPD / SPERMIDINE / N-(2-AMINO-PROPYL)-1,4-DIAMINOBUTANE / PA(34)


Mass: 145.246 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C7H19N3
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-BME / BETA-MERCAPTOETHANOL


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS
#6: Chemical ChemComp-OXM / OXAMIC ACID


Mass: 89.050 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C2H3NO3
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 380 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN

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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: 3.11 Å3/Da / Density % sol: 60.4 %
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: Oct 18, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.66→46.01 Å / Num. obs: 120759 / % possible obs: 99.9 % / Redundancy: 10.087 % / Biso Wilson estimate: 33.796 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.162 / Rrim(I) all: 0.17 / Χ2: 1.069 / Net I/σ(I): 9.47 / Num. measured all: 1218148
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
1.66-1.7610.0743.6150.5519393919351192520.4623.80999.5
1.76-1.8810.2572.1021.0118667618205181990.7162.213100
1.88-2.039.631.1061.9316338716971169670.8721.168100
2.03-2.2310.4550.5763.8816379315670156660.9590.606100
2.23-2.4910.2240.336.9114505514192141880.9840.348100
2.49-2.8710.0540.18312.0312622912556125550.9940.192100
2.87-3.5110.2840.09422.3111026710722107220.9980.099100
3.51-4.959.8710.05437.9782644837683720.9990.057100
4.95-46.019.5410.04644.3346158484748380.9990.04999.8

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Processing

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

6xxj


Resolution: 1.66→46.01 Å / SU ML: 0.28 / Cross valid method: THROUGHOUT / σ(F): 1.32 / Phase error: 26.05 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1926 2096 1.74 %
Rwork0.1706 118421 -
obs0.171 120517 99.7 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 219.54 Å2 / Biso mean: 41.8252 Å2 / Biso min: 18 Å2
Refinement stepCycle: final / Resolution: 1.66→46.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5179 0 276 380 5835
Biso mean--49.48 45.84 -
Num. residues----664
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 (%)
1.66-1.70.47951360.45587691782798
1.7-1.740.41621390.38637791793099
1.74-1.790.38781380.350778277965100
1.79-1.840.32171380.316478577995100
1.84-1.90.29641380.284677947932100
1.9-1.970.29311390.241878217960100
1.97-2.050.25291390.211978557994100
2.05-2.140.22471390.186778808019100
2.14-2.250.19891390.164778457984100
2.25-2.390.16371400.151679358075100
2.39-2.580.17831390.134278688007100
2.58-2.840.14981410.130879578098100
2.84-3.250.14491410.135179608101100
3.25-4.090.15151420.134180398181100
4.09-46.010.17331480.155583018449100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
16.96452.51571.49364.0260.5493.12850.00620.16060.3589-0.23450.0366-0.2305-0.6485-0.11360.02050.49010.10330.02230.23320.05210.2583-38.4861-16.0068-6.744
22.37840.27060.34521.5637-0.48191.44090.1510.61930.3042-0.5444-0.0974-0.3417-0.48660.2431-0.17890.60520.02810.11830.32160.07890.3403-19.721-17.7766-24.643
32.3696-0.01780.26361.18930.29131.6763-0.00070.43610.2123-0.52790.0067-0.3573-0.3710.1812-0.02520.52890.0380.06810.34510.02380.2479-19.2973-29.2939-27.9772
40.7159-0.298-0.00660.80960.06140.93970.1510.1806-0.0113-0.2615-0.1423-0.015-0.03440.0362-0.00010.4110.06870.00090.30010.00750.2035-19.6708-41.2086-27.2109
51.9245-0.377-0.01260.90150.28911.37950.0386-0.10520.3639-0.083-0.049-0.1648-0.3040.2005-0.03190.4032-0.03690.02750.27150.00740.3069-12.7385-24.8569-9.7508
64.08781.6873-0.41782.1576-3.47567.6050.15840.49150.4961-0.00560.02050.4595-0.3406-0.5108-0.10930.44680.09940.00490.29740.04560.2661-31.8225-23.1058-22.4698
72.0517-0.5779-0.3933.02191.78194.06720.1242-0.0862-0.2271-0.12420.0636-0.12660.40510.2974-0.18350.27510.023-0.03370.28770.05270.2188-6.9785-57.39986.8132
80.6971-0.12170.14090.7204-0.03391.33280.1180.08930.0661-0.1548-0.072-0.1609-0.00590.3842-0.04230.26470.02130.03410.33830.01350.2241-1.6254-44.4683-12.6604
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 28 through 53 )A28 - 53
2X-RAY DIFFRACTION2chain 'A' and (resid 54 through 88 )A54 - 88
3X-RAY DIFFRACTION3chain 'A' and (resid 89 through 110 )A89 - 110
4X-RAY DIFFRACTION4chain 'A' and (resid 111 through 307 )A111 - 307
5X-RAY DIFFRACTION5chain 'A' and (resid 308 through 342 )A308 - 342
6X-RAY DIFFRACTION6chain 'A' and (resid 343 through 363 )A343 - 363
7X-RAY DIFFRACTION7chain 'B' and (resid 28 through 97 )B28 - 97
8X-RAY DIFFRACTION8chain 'B' and (resid 98 through 364 )B98 - 364

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