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- PDB-8qaw: Medicago truncatula HISN5 (IGPD) in complex with MN, IMD, EDO, FM... -

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Basic information

Entry
Database: PDB / ID: 8qaw
TitleMedicago truncatula HISN5 (IGPD) in complex with MN, IMD, EDO, FMT, GOL and TRS
ComponentsImidazoleglycerol-phosphate dehydratase
KeywordsLYASE / HISN5 / IGPD / histidine biosynthesis
Function / homology
Function and homology information


imidazoleglycerol-phosphate dehydratase / imidazoleglycerol-phosphate dehydratase activity / L-histidine biosynthetic process
Similarity search - Function
Imidazoleglycerol-phosphate dehydratase signature 1. / Imidazoleglycerol-phosphate dehydratase / Imidazoleglycerol-phosphate dehydratase, conserved site / Imidazole glycerol phosphate dehydratase domain superfamily / Imidazoleglycerol-phosphate dehydratase / Imidazoleglycerol-phosphate dehydratase signature 2. / Ribosomal protein S5 domain 2-type fold
Similarity search - Domain/homology
FORMIC ACID / IMIDAZOLE / : / Imidazoleglycerol-phosphate dehydratase
Similarity search - Component
Biological speciesMedicago truncatula (barrel medic)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.55 Å
AuthorsWitek, W. / Ruszkowski, M.
Funding support Poland, 1items
OrganizationGrant numberCountry
Polish National Science CentreSonata 2018/31/D/NZ1/03630 Poland
CitationJournal: Front Plant Sci / Year: 2024
Title: Targeting imidazole-glycerol phosphate dehydratase in plants: novel approach for structural and functional studies, and inhibitor blueprinting.
Authors: Wojciech Witek / Joanna Sliwiak / Michal Rawski / Milosz Ruszkowski /
Abstract: The histidine biosynthetic pathway (HBP) is targeted for herbicide design with preliminary success only regarding imidazole-glycerol phosphate dehydratase (IGPD, EC 4.2.1.19), or HISN5, as referred ...The histidine biosynthetic pathway (HBP) is targeted for herbicide design with preliminary success only regarding imidazole-glycerol phosphate dehydratase (IGPD, EC 4.2.1.19), or HISN5, as referred to in plants. HISN5 catalyzes the sixth step of the HBP, in which imidazole-glycerol phosphate (IGP) is dehydrated to imidazole-acetol phosphate. In this work, we present high-resolution cryoEM and crystal structures of HISN5 (HISN5) in complexes with an inactive IGP diastereoisomer and with various other ligands. HISN5 can serve as a new model for plant HISN5 structural studies, as it enables resolving protein-ligand interactions at high (2.2 Å) resolution using cryoEM. We identified ligand-binding hotspots and characterized the features of plant HISN5 enzymes in the context of the HISN5-targeted inhibitor design. Virtual screening performed against millions of small molecules not only revealed candidate molecules but also identified linkers for fragments that were experimentally confirmed to bind. Based on experimental and computational approaches, this study provides guidelines for designing symmetric HISN5 inhibitors that can reach two neighboring active sites. Finally, we conducted analyses of sequence similarity networks revealing that plant HISN5 enzymes derive from cyanobacteria. We also adopted a new approach to measure HISN5 enzymatic activity using isothermal titration calorimetry and enzymatically synthesized IGP.
History
DepositionAug 23, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 10, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Imidazoleglycerol-phosphate dehydratase
B: Imidazoleglycerol-phosphate dehydratase
C: Imidazoleglycerol-phosphate dehydratase
D: Imidazoleglycerol-phosphate dehydratase
E: Imidazoleglycerol-phosphate dehydratase
F: Imidazoleglycerol-phosphate dehydratase
G: Imidazoleglycerol-phosphate dehydratase
H: Imidazoleglycerol-phosphate dehydratase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)185,13083
Polymers180,5708
Non-polymers4,56075
Water24,0501335
1
A: Imidazoleglycerol-phosphate dehydratase
B: Imidazoleglycerol-phosphate dehydratase
C: Imidazoleglycerol-phosphate dehydratase
D: Imidazoleglycerol-phosphate dehydratase
E: Imidazoleglycerol-phosphate dehydratase
F: Imidazoleglycerol-phosphate dehydratase
G: Imidazoleglycerol-phosphate dehydratase
H: Imidazoleglycerol-phosphate dehydratase
hetero molecules

A: Imidazoleglycerol-phosphate dehydratase
B: Imidazoleglycerol-phosphate dehydratase
C: Imidazoleglycerol-phosphate dehydratase
D: Imidazoleglycerol-phosphate dehydratase
E: Imidazoleglycerol-phosphate dehydratase
F: Imidazoleglycerol-phosphate dehydratase
G: Imidazoleglycerol-phosphate dehydratase
H: Imidazoleglycerol-phosphate dehydratase
hetero molecules

A: Imidazoleglycerol-phosphate dehydratase
B: Imidazoleglycerol-phosphate dehydratase
C: Imidazoleglycerol-phosphate dehydratase
D: Imidazoleglycerol-phosphate dehydratase
E: Imidazoleglycerol-phosphate dehydratase
F: Imidazoleglycerol-phosphate dehydratase
G: Imidazoleglycerol-phosphate dehydratase
H: Imidazoleglycerol-phosphate dehydratase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)555,390249
Polymers541,71124
Non-polymers13,679225
Water43224
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-y,x-y,z1
crystal symmetry operation3_555-x+y,-x,z1
Unit cell
Length a, b, c (Å)137.680, 137.680, 265.907
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number146
Space group name H-MH3
Space group name HallR3
Symmetry operation#1: x,y,z
#2: -y,x-y,z
#3: -x+y,-x,z
#4: x+1/3,y+2/3,z+2/3
#5: -y+1/3,x-y+2/3,z+2/3
#6: -x+y+1/3,-x+2/3,z+2/3
#7: x+2/3,y+1/3,z+1/3
#8: -y+2/3,x-y+1/3,z+1/3
#9: -x+y+2/3,-x+1/3,z+1/3
Components on special symmetry positions
IDModelComponents
11A-309-

TRS

21A-309-

TRS

31D-311-

TRS

41D-311-

TRS

Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "A" and (resid 77 through 92 or resid 94...
d_2ens_1(chain "B" and (resid 77 through 92 or resid 94...
d_3ens_1(chain "C" and (resid 77 through 92 or resid 94...
d_4ens_1(chain "D" and (resid 77 through 92 or resid 94...
d_5ens_1(chain "E" and (resid 77 through 92 or resid 94...
d_6ens_1(chain "F" and (resid 77 through 92 or resid 94...
d_7ens_1(chain "G" and (resid 77 through 92 or resid 94...
d_8ens_1(chain "H" and (resid 77 through 92 or resid 94...

NCS domain segments:

Ens-ID: ens_1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11GLYGLYVALVALAA77 - 928 - 23
d_12VALVALASNASNAA94 - 10625 - 37
d_13SERSERVALVALAA108 - 12839 - 59
d_14VALVALLEULEUAA130 - 15661 - 87
d_15ALAALAARGARGAA158 - 26089 - 191
d_16FMTFMTFMTFMTAJ302
d_21GLYGLYVALVALBB77 - 928 - 23
d_22VALVALASNASNBB94 - 10625 - 37
d_23SERSERVALVALBB108 - 12839 - 59
d_24VALVALLEULEUBB130 - 15661 - 87
d_25ALAALAARGARGBB158 - 26089 - 191
d_26FMTFMTFMTFMTBU302
d_31GLYGLYVALVALCC77 - 928 - 23
d_32VALVALASNASNCC94 - 10625 - 37
d_33SERSERVALVALCC108 - 12839 - 59
d_34VALVALLEULEUCC130 - 15661 - 87
d_35ALAALAARGARGCC158 - 26089 - 191
d_36FMTFMTFMTFMTCFA302
d_41GLYGLYVALVALDD77 - 928 - 23
d_42VALVALASNASNDD94 - 10625 - 37
d_43SERSERVALVALDD108 - 12839 - 59
d_44VALVALLEULEUDD130 - 15661 - 87
d_45ALAALAARGARGDD158 - 26089 - 191
d_46FMTFMTFMTFMTDQA303
d_51GLYGLYVALVALEE77 - 928 - 23
d_52VALVALASNASNEE94 - 10625 - 37
d_53SERSERVALVALEE108 - 12839 - 59
d_54VALVALLEULEUEE130 - 15661 - 87
d_55ALAALAARGARGEE158 - 26089 - 191
d_56FMTFMTFMTFMTEBB303
d_61GLYGLYVALVALFF77 - 928 - 23
d_62VALVALASNASNFF94 - 10625 - 37
d_63SERSERVALVALFF108 - 12839 - 59
d_64VALVALLEULEUFF130 - 15661 - 87
d_65ALAALAARGARGFF158 - 26089 - 191
d_66FMTFMTFMTFMTFJB302
d_71GLYGLYVALVALGG77 - 928 - 23
d_72VALVALASNASNGG94 - 10625 - 37
d_73SERSERVALVALGG108 - 12839 - 59
d_74VALVALLEULEUGG130 - 15661 - 87
d_75ALAALAARGARGGG158 - 26089 - 191
d_76FMTFMTFMTFMTGQB302
d_81GLYGLYVALVALHH77 - 928 - 23
d_82VALVALASNASNHH94 - 10625 - 37
d_83SERSERVALVALHH108 - 12839 - 59
d_84VALVALLEULEUHH130 - 15661 - 87
d_85ALAALAARGARGHH158 - 26089 - 191
d_86FMTFMTFMTFMTHYB302

NCS oper:
IDCodeMatrixVector
1given(0.0812201785908, -0.368913917921, -0.925908096818), (0.799705353435, 0.578576788849, -0.160375331933), (0.594873625468, -0.727427948714, 0.342014545237)123.65594269, 21.3290210237, 87.7563703711
2given(0.802242957297, 0.496033842859, -0.332199735409), (-0.071315417931, -0.472840021718, -0.87825760744), (-0.592722826144, 0.728266943229, -0.343957716541)44.2869894804, 117.244926185, 178.293904577
3given(0.192569662331, 0.981261899434, -0.00648150198826), (0.981283254342, -0.192563324143, 0.00159403332398), (0.000316064598956, -0.00666715182301, -0.999977724347)0.717577288455, -0.158611952676, 266.11343321
4given(0.0858106363611, 0.801890666357, 0.591276495302), (-0.359202242525, 0.578453395625, -0.732369727702), (-0.929306345428, -0.149542730679, 0.3376783796)-79.0849176096, 97.5587647003, 88.0629155461
5given(0.270079971702, 0.238799573422, -0.932754829855), (-0.903591602758, 0.397440635856, -0.159884822278), (0.332534245319, 0.886011119966, 0.323118044972)124.384383556, 21.1874384646, 89.5629626691
6given(-0.834587523294, 0.438820106028, -0.333017387696), (0.437651154466, 0.161043859578, -0.884605190063), (-0.334552137876, -0.88402589885, -0.326455321913)44.306995548, 117.950522015, 176.618433541
7given(-0.335360977129, 0.722544008611, -0.6045354999), (0.153206791383, 0.674982400969, 0.721752338033), (0.92954865074, 0.149428625112, -0.337061406726)80.5256556651, -96.3559678929, 177.763706743

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Components

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Protein , 1 types, 8 molecules ABCDEFGH

#1: Protein
Imidazoleglycerol-phosphate dehydratase /


Mass: 22571.293 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Medicago truncatula (barrel medic) / Production host: Escherichia coli (E. coli) / References: UniProt: I3SDM5

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Non-polymers , 9 types, 1410 molecules

#2: Chemical
ChemComp-IMD / IMIDAZOLE / Imidazole


Mass: 69.085 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C3H5N2
#3: Chemical
ChemComp-FMT / FORMIC ACID / Formic acid


Mass: 46.025 Da / Num. of mol.: 11 / Source method: obtained synthetically / Formula: CH2O2
#4: Chemical...
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 31 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical
ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: Mn
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#7: Chemical
ChemComp-TRS / 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / TRIS BUFFER / Tris


Mass: 122.143 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C4H12NO3 / Comment: pH buffer*YM
#8: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#9: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#10: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1335 / 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: 2.98 Å3/Da / Density % sol: 58.69 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.2M Sodium formate; 0.2M Ammonium acetate; 0.2M Sodium citrate tribasic dihydrate; 0.2M Potassium sodium tartrate tetrahydrate; 0.2M Sodium oxamate; 1.0M Imidazole; 1.0M MES monohydrate ...Details: 0.2M Sodium formate; 0.2M Ammonium acetate; 0.2M Sodium citrate tribasic dihydrate; 0.2M Potassium sodium tartrate tetrahydrate; 0.2M Sodium oxamate; 1.0M Imidazole; 1.0M MES monohydrate (acid); 40% v/v Glycerol; 20% w/v PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, EMBL c/o DESY / Beamline: P13 (MX1) / Wavelength: 0.9762 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 21, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9762 Å / Relative weight: 1
ReflectionResolution: 1.55→80 Å / Num. obs: 272024 / % possible obs: 99.9 % / Redundancy: 11 % / Biso Wilson estimate: 23.29 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.105 / Rrim(I) all: 0.11 / Net I/σ(I): 11.9
Reflection shellResolution: 1.55→1.65 Å / Rmerge(I) obs: 0.97 / Mean I/σ(I) obs: 1.8 / Num. unique obs: 43832 / CC1/2: 0.83 / Rrim(I) all: 1

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Processing

Software
NameVersionClassification
XDSdata reduction
PHASERphasing
PHENIX1.20.1_4487refinement
Coot0.9.8.8model building
XDSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.55→58.06 Å / SU ML: 0.1539 / Cross valid method: FREE R-VALUE / Phase error: 18.4209
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1614 1088 0.4 %
Rwork0.1288 270785 -
obs0.129 271873 99.87 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 31.37 Å2
Refinement stepCycle: LAST / Resolution: 1.55→58.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11469 0 255 1335 13059
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.004911921
X-RAY DIFFRACTIONf_angle_d0.795716039
X-RAY DIFFRACTIONf_chiral_restr0.05271805
X-RAY DIFFRACTIONf_plane_restr0.0052106
X-RAY DIFFRACTIONf_dihedral_angle_d12.32894262
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AAX-RAY DIFFRACTIONTorsion NCS0.45317645875
ens_1d_3AAX-RAY DIFFRACTIONTorsion NCS0.381093190449
ens_1d_4AAX-RAY DIFFRACTIONTorsion NCS0.399088024552
ens_1d_5AAX-RAY DIFFRACTIONTorsion NCS0.607636194217
ens_1d_6AAX-RAY DIFFRACTIONTorsion NCS0.399622277276
ens_1d_7AAX-RAY DIFFRACTIONTorsion NCS0.408606688021
ens_1d_8AAX-RAY DIFFRACTIONTorsion NCS0.32788531134
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.55-1.620.23331360.212533654X-RAY DIFFRACTION99.25
1.62-1.710.22421360.171133797X-RAY DIFFRACTION99.9
1.71-1.810.2131360.148733893X-RAY DIFFRACTION99.91
1.81-1.950.14871360.113633920X-RAY DIFFRACTION99.96
1.95-2.150.1941360.113733852X-RAY DIFFRACTION99.97
2.15-2.460.17821360.122633889X-RAY DIFFRACTION99.99
2.46-3.10.14831360.132533850X-RAY DIFFRACTION100
3.1-58.060.14171360.124333930X-RAY DIFFRACTION99.96

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