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- PDB-8qzw: Crystal structure of deoxyhypusine synthase from Trichomonas vaginalis -

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Basic information

Entry
Database: PDB / ID: 8qzw
TitleCrystal structure of deoxyhypusine synthase from Trichomonas vaginalis
ComponentsDeoxyhypusine synthase related protein, putative
KeywordsTRANSFERASE / translation / hypusination / hypusine / eIF5A / deoxyhypusine / deoxyhypusination
Function / homologydeoxyhypusine synthase activity / Deoxyhypusine synthase / Deoxyhypusine synthase superfamily / Deoxyhypusine synthase / DHS-like NAD/FAD-binding domain superfamily / cytoplasm / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / Deoxyhypusine synthase related protein, putative
Function and homology information
Biological speciesTrichomonas vaginalis (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.68 Å
AuthorsWator, E. / Wilk, P. / Grudnik, P.
Funding support Poland, 2items
OrganizationGrant numberCountry
Polish National Science Centre2019/35/N/NZ1/02805 Poland
Polish National Science CentreUMO-2019/33/B/NZ1/01839 Poland
CitationJournal: FEBS J / Year: 2024
Title: Structural characterization of the (deoxy)hypusination in Trichomonas vaginalis questions the bifunctionality of deoxyhypusine synthase.
Authors: Elżbieta Wątor / Piotr Wilk / Paweł Kochanowski / Przemysław Grudnik /
Abstract: Trichomonas vaginalis, the causative agent of trichomoniasis, is a prevalent anaerobic protozoan parasite responsible for the most common nonviral sexually transmitted infection globally. While ...Trichomonas vaginalis, the causative agent of trichomoniasis, is a prevalent anaerobic protozoan parasite responsible for the most common nonviral sexually transmitted infection globally. While metronidazole and its derivatives are approved drugs for this infection, rising resistance necessitates the exploration of new antiparasitic therapies. Protein posttranslational modifications (PTMs) play crucial roles in cellular processes, and among them, hypusination, involving eukaryotic translation factor 5A (eIF5A), has profound implications. Despite extensive studies in various organisms, the role of hypusination in T. vaginalis and its potential impact on parasite biology and pathogenicity remain poorly understood. This study aims to unravel the structural basis of the hypusination pathway in T. vaginalis using X-ray crystallography and cryo-electron microscopy. The results reveal high structural homology between T. vaginalis and human orthologs, providing insights into the molecular architecture of eIF5A and deoxyhypusine synthase (DHS) and their interaction. Contrary to previous suggestions of bifunctionality, our analyses indicate that the putative hydroxylation site in tvDHS is nonfunctional, and biochemical assays demonstrate exclusive deoxyhypusination capability. These findings challenge the notion of tvDHS functioning as both deoxyhypusine synthase and hydroxylase. The study enhances understanding of the hypusination pathway in T. vaginalis, shedding light on its functional relevance and potential as a drug target, and contributing to the development of novel therapeutic strategies against trichomoniasis.
History
DepositionOct 30, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 3, 2024Provider: repository / Type: Initial release
Revision 1.1Jul 10, 2024Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Deoxyhypusine synthase related protein, putative
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,28413
Polymers40,5791
Non-polymers1,70412
Water7,206400
1
A: Deoxyhypusine synthase related protein, putative
hetero molecules

A: Deoxyhypusine synthase related protein, putative
hetero molecules

A: Deoxyhypusine synthase related protein, putative
hetero molecules

A: Deoxyhypusine synthase related protein, putative
hetero molecules


Theoretical massNumber of molelcules
Total (without water)169,13452
Polymers162,3174
Non-polymers6,81748
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_455y-1/2,x+1/2,-z+1/21
crystal symmetry operation10_565-x,-y+1,z1
crystal symmetry operation16_555-y+1/2,-x+1/2,-z+1/21
Buried area45190 Å2
ΔGint-631 kcal/mol
Surface area41420 Å2
MethodPISA
Unit cell
Length a, b, c (Å)123.145, 123.145, 263.326
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number98
Space group name H-MI4122
Components on special symmetry positions
IDModelComponents
11A-406-

SO4

21A-843-

HOH

31A-894-

HOH

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Components

#1: Protein Deoxyhypusine synthase related protein, putative


Mass: 40579.270 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Trichomonas vaginalis (eukaryote) / Strain: BL21(DE3) / Gene: TVAG_359990 / Variant: Rosetta / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Rosetta / References: UniProt: A2DTB8
#2: Chemical ChemComp-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE


Mass: 663.425 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: NAD*YM
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 400 / 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: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 6.16 Å3/Da / Density % sol: 80.02 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: Proplex G3: 0.1M HEPES pH 7.0; 2M (NH4)2SO4

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: 2019-11-09 / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 9, 2019
RadiationMonochromator: DCM / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.68→48.42 Å / Num. obs: 114945 / % possible obs: 99.6 % / Redundancy: 14.67 % / Biso Wilson estimate: 35.48 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.101 / Rrim(I) all: 0.104 / Net I/av σ(I): 17.99 / Net I/σ(I): 17.99
Reflection shellResolution: 1.68→1.78 Å / Redundancy: 14.4 % / Rmerge(I) obs: 2.443 / Mean I/σ(I) obs: 0.95 / Num. unique obs: 18031 / CC1/2: 0.624 / Rrim(I) all: 2.532 / % possible all: 97.7

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
PHASERphasing
XDSdata reduction
XDSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.68→48.42 Å / SU ML: 0.19 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 18.96 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1553 2097 1.83 %
Rwork0.1484 --
obs0.1485 114807 99.48 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.68→48.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2815 0 103 400 3318
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.013
X-RAY DIFFRACTIONf_angle_d1.15
X-RAY DIFFRACTIONf_dihedral_angle_d14.7031102
X-RAY DIFFRACTIONf_chiral_restr0.065440
X-RAY DIFFRACTIONf_plane_restr0.008515
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.68-1.720.36221300.37417011X-RAY DIFFRACTION94
1.72-1.760.28461370.3147429X-RAY DIFFRACTION100
1.76-1.810.28131390.29267450X-RAY DIFFRACTION100
1.81-1.860.21641380.24927456X-RAY DIFFRACTION100
1.86-1.920.29541400.22837467X-RAY DIFFRACTION100
1.92-1.990.22281390.18577487X-RAY DIFFRACTION100
1.99-2.070.17371390.16927475X-RAY DIFFRACTION100
2.07-2.160.16951400.15647526X-RAY DIFFRACTION100
2.16-2.270.16571400.147492X-RAY DIFFRACTION100
2.27-2.420.13391400.13567553X-RAY DIFFRACTION100
2.42-2.60.15621400.1297523X-RAY DIFFRACTION100
2.6-2.870.13931420.13297602X-RAY DIFFRACTION100
2.87-3.280.141410.13227596X-RAY DIFFRACTION100
3.28-4.130.12321430.12347683X-RAY DIFFRACTION100
4.13-48.420.14711490.14047960X-RAY DIFFRACTION100

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