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

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Basic information

Entry
Database: PDB / ID: 7zii
TitleCrystal structure of human tryptophan hydroxylase 1 in complex with inhibitor KM-05-193
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-IVQ / Tryptophan 5-hydroxylase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.62800050605 Å
AuthorsSchuetz, A. / Mallow, K. / 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)38,0314
Polymers37,4251
Non-polymers6063
Water5,657314
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area210 Å2
ΔGint-1 kcal/mol
Surface area12910 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.97, 57.947, 59.349
Angle α, β, γ (deg.)90.0, 97.624, 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-IVQ / 8-(5~{H}-[1,3]dioxolo[4,5-f]benzimidazol-6-ylmethyl)-7-(phenylmethyl)-3-propyl-purine-2,6-dione


Mass: 458.469 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H22N6O4 / 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.: 314 / 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: 42.45 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / Details: 20% w/v PEG 3350, 200 mM potassium formate pH 7.3

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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: Jul 19, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.628→29.5515963785 Å / Num. obs: 39546 / % possible obs: 99.66 % / Redundancy: 4.5 % / Biso Wilson estimate: 17.8251303948 Å2 / Rmerge(I) obs: 0.0669 / Net I/σ(I): 14.71
Reflection shellResolution: 1.63→1.69 Å / Rmerge(I) obs: 0.7235 / Num. unique obs: 3859

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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: 1.62800050605→29.5515963785 Å / SU ML: 0.169431605722 / Cross valid method: FREE R-VALUE / σ(F): 1.3544379811 / Phase error: 20.1215586376
RfactorNum. reflection% reflection
Rfree0.191912784114 1977 4.99987354897 %
Rwork0.16709833574 37564 -
obs0.168344186808 39541 99.6672800141 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 25.8363252539 Å2
Refinement stepCycle: LAST / Resolution: 1.62800050605→29.5515963785 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2322 0 41 314 2677
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.009216100266662433
X-RAY DIFFRACTIONf_angle_d1.199146260043292
X-RAY DIFFRACTIONf_chiral_restr0.0575745316211343
X-RAY DIFFRACTIONf_plane_restr0.00656787179496421
X-RAY DIFFRACTIONf_dihedral_angle_d11.5365241098907
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.62800050605-1.66870.2860008151831360.2516184028692572X-RAY DIFFRACTION96.9566774078
1.6687-1.71380.2331017467011410.2303807647552691X-RAY DIFFRACTION99.9294283698
1.7138-1.76420.2838608052141410.2197321504072678X-RAY DIFFRACTION99.9291031549
1.7642-1.82120.2502147999981410.2137985526622666X-RAY DIFFRACTION99.7158081705
1.8212-1.88630.2267322710511400.2066274371752665X-RAY DIFFRACTION99.8576005696
1.8863-1.96180.235917961741420.1923335774022705X-RAY DIFFRACTION99.9297999298
1.9618-2.0510.207262677931400.1754348821772664X-RAY DIFFRACTION99.8575498575
2.051-2.15910.2120312275181410.1715630286462669X-RAY DIFFRACTION99.8933522929
2.1591-2.29440.2036277994821420.1706989188882700X-RAY DIFFRACTION99.9648258881
2.2944-2.47140.211574833411420.1704766834742703X-RAY DIFFRACTION100
2.4714-2.720.1910441970521410.1666309299322676X-RAY DIFFRACTION99.8936170213
2.72-3.11320.1949553866071430.162468262382714X-RAY DIFFRACTION99.9650104969
3.1132-3.92090.1607172826251430.1424052133972717X-RAY DIFFRACTION99.8603351955

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