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- PDB-7zif: Crystal structure of human tryptophan hydroxylase 1 in complex wi... -

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Basic information

Entry
Database: PDB / ID: 7zif
TitleCrystal structure of human tryptophan hydroxylase 1 in complex with inhibitor KM-480
ComponentsTryptophan 5-hydroxylase 1
KeywordsMETAL BINDING PROTEIN / tryptophan hydroxylase / serotonin biosynthesis
Function / homology
Function and homology information


regulation of hemostasis / tryptophan 5-monooxygenase / tryptophan 5-monooxygenase activity / Serotonin and melatonin biosynthesis / aromatic amino acid metabolic process / serotonin biosynthetic process / platelet degranulation / NGF-stimulated transcription / bone remodeling / mammary gland alveolus development ...regulation of hemostasis / tryptophan 5-monooxygenase / tryptophan 5-monooxygenase activity / Serotonin and melatonin biosynthesis / aromatic amino acid metabolic process / serotonin biosynthetic process / platelet degranulation / NGF-stimulated transcription / bone remodeling / mammary gland alveolus development / positive regulation of fat cell differentiation / neuron projection / iron ion binding / cytosol
Similarity search - Function
Tryptophan 5-monooxygenase / Tryptophan 5-hydroxylase, catalytic domain / Tyrosine 3-monooxygenase-like / Aromatic amino acid hydroxylase, iron/copper binding site / Biopterin-dependent aromatic amino acid hydroxylases signature. / Aromatic amino acid hydroxylase / Aromatic amino acid hydroxylase, C-terminal / Aromatic amino acid monoxygenase, C-terminal domain superfamily / Aromatic amino acid hydroxylase superfamily / Biopterin-dependent aromatic amino acid hydroxylase ...Tryptophan 5-monooxygenase / Tryptophan 5-hydroxylase, catalytic domain / Tyrosine 3-monooxygenase-like / Aromatic amino acid hydroxylase, iron/copper binding site / Biopterin-dependent aromatic amino acid hydroxylases signature. / Aromatic amino acid hydroxylase / Aromatic amino acid hydroxylase, C-terminal / Aromatic amino acid monoxygenase, C-terminal domain superfamily / Aromatic amino acid hydroxylase superfamily / Biopterin-dependent aromatic amino acid hydroxylase / Biopterin-dependent aromatic amino acid hydroxylase family profile. / ACT domain profile. / ACT domain / ACT-like domain
Similarity search - Domain/homology
: / Chem-IWA / Tryptophan 5-hydroxylase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.86859719255 Å
AuthorsSchuetz, A. / Ziebart, N. / Weise, M. / Mallow, K. / Pfeifer, J. / Nazare, M. / Specker, E. / Heinemann, U.
Funding support Germany, 1items
OrganizationGrant numberCountry
Helmholtz Association Germany
CitationJournal: J.Med.Chem. / Year: 2022
Title: Structure-Based Design of Xanthine-Benzimidazole Derivatives as Novel and Potent Tryptophan Hydroxylase Inhibitors.
Authors: Specker, E. / Matthes, S. / Wesolowski, R. / Schutz, A. / Grohmann, M. / Alenina, N. / Pleimes, D. / Mallow, K. / Neuenschwander, M. / Gogolin, A. / Weise, M. / Pfeifer, J. / Ziebart, N. / ...Authors: Specker, E. / Matthes, S. / Wesolowski, R. / Schutz, A. / Grohmann, M. / Alenina, N. / Pleimes, D. / Mallow, K. / Neuenschwander, M. / Gogolin, A. / Weise, M. / Pfeifer, J. / Ziebart, N. / Heinemann, U. / von Kries, J.P. / Nazare, M. / Bader, M.
History
DepositionApr 8, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 7, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 31, 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

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Assembly

Deposited unit
A: Tryptophan 5-hydroxylase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1214
Polymers37,4251
Non-polymers6973
Water4,089227
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area130 Å2
ΔGint1 kcal/mol
Surface area12720 Å2
Unit cell
Length a, b, c (Å)47.021, 57.919, 59.416
Angle α, β, γ (deg.)90.0, 97.654, 90.0
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Protein Tryptophan 5-hydroxylase 1 / Tryptophan 5-monooxygenase 1


Mass: 37424.602 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: catalytic domain of human TPH1 / Source: (gene. exp.) Homo sapiens (human) / Gene: TPH1, TPH, TPRH, TRPH / Production host: Escherichia coli (E. coli) / References: UniProt: P17752, tryptophan 5-monooxygenase
#2: Chemical ChemComp-FE / FE (III) ION


Mass: 55.845 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Fe
#3: Chemical ChemComp-IWA / (2R)-2-azanyl-5-[[2-[3-methyl-2,6-bis(oxidanylidene)-7-(phenylmethyl)purin-8-yl]sulfanyl-3H-benzimidazol-5-yl]amino]-5-oxidanylidene-pentanoic acid


Mass: 548.574 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H24N8O5S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 227 / 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: 2.14 Å3/Da / Density % sol: 42.55 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / Details: 8% w/v PEG 8000, 100 mM Tris-HCl 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: Jan 28, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.868597→41.2928 Å / Num. obs: 26286 / % possible obs: 99.76 % / Redundancy: 4.1 % / Biso Wilson estimate: 20.1733245887 Å2 / Rmerge(I) obs: 0.0704 / Net I/σ(I): 14.53
Reflection shellResolution: 1.87→1.94 Å / Redundancy: 3.9 % / Rmerge(I) obs: 0.4426 / Num. unique obs: 2564 / % possible all: 98.69

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1mlw

1mlw


Resolution: 1.86859719255→41.2927756871 Å / SU ML: 0.192895501794 / Cross valid method: FREE R-VALUE / σ(F): 1.3674232932 / Phase error: 20.9285169768
RfactorNum. reflection% reflection
Rfree0.198808711011 1314 4.99961951145 %
Rwork0.159509235052 24968 -
obs0.161484691984 26282 99.7495066039 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 25.8132692447 Å2
Refinement stepCycle: LAST / Resolution: 1.86859719255→41.2927756871 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2352 0 46 227 2625
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01001081603682475
X-RAY DIFFRACTIONf_angle_d1.260294446343351
X-RAY DIFFRACTIONf_chiral_restr0.0526172345904348
X-RAY DIFFRACTIONf_plane_restr0.00685206122876431
X-RAY DIFFRACTIONf_dihedral_angle_d12.516595896927
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8686-1.94340.2731380010821420.2080591045622702X-RAY DIFFRACTION98.8186240445
1.9434-2.03190.2602143341871460.1826022399252769X-RAY DIFFRACTION99.8971898561
2.0319-2.1390.24080822021470.1810296802922794X-RAY DIFFRACTION99.9320421339
2.139-2.2730.2248518021051440.1701156809132735X-RAY DIFFRACTION99.7920277296
2.273-2.44850.2198152054611460.1671807858462770X-RAY DIFFRACTION99.931459904
2.4485-2.69480.226038992971460.1641572901312780X-RAY DIFFRACTION99.8975759645
2.6948-3.08470.2070171272781460.159756912362777X-RAY DIFFRACTION99.8633413051
3.0847-3.88590.1749799421291470.1460560141262801X-RAY DIFFRACTION99.9660902001

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