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- PDB-8cjl: Crystal structure of human tryptophan hydroxylase 1 in complex wi... -

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Basic information

Entry
Database: PDB / ID: 8cjl
TitleCrystal structure of human tryptophan hydroxylase 1 in complex with inhibitor TPT-004
ComponentsTryptophan 5-hydroxylase 1
KeywordsMETAL BINDING PROTEIN / catalytic domain of human tryptophan hydroxylase 1 (TPH1) / inhibitor complex
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-UXC / Tryptophan 5-hydroxylase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.83 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: 2023
Title: Structure-Based Design of Xanthine-Imidazopyridines and -Imidazothiazoles as Highly Potent and In Vivo Efficacious Tryptophan Hydroxylase Inhibitors.
Authors: Specker, E. / Wesolowski, R. / Schutz, A. / Matthes, S. / Mallow, K. / Wasinska-Kalwa, M. / Winkler, L. / Oder, A. / Alenina, N. / Pleimes, D. / von Kries, J.P. / Heinemann, U. / Bader, M. / Nazare, M.
History
DepositionFeb 13, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 10, 2024Provider: repository / Type: Initial release

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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)37,8813
Polymers37,4251
Non-polymers4562
Water4,918273
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area140 Å2
ΔGint-14 kcal/mol
Surface area12630 Å2
MethodPISA
Unit cell
Length a, b, c (Å)47.090, 58.090, 65.290
Angle α, β, γ (deg.)90.000, 103.570, 90.000
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
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 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-UXC / 3-ethyl-8-[(2-methyl-5~{H}-imidazo[2,1-b][1,3]thiazol-6-yl)methyl]-7-(oxetan-3-ylmethyl)purine-2,6-dione


Mass: 400.455 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H20N6O3S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 273 / 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: 2.32 Å3/Da / Density % sol: 46.97 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / Details: 18% PEG6000, 0.1 M Tris 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: Aug 31, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.83→45.78 Å / Num. obs: 30237 / % possible obs: 99.52 % / Redundancy: 4 % / Biso Wilson estimate: 25.8 Å2 / CC1/2: 0.994 / Net I/σ(I): 6.84
Reflection shellResolution: 1.83→1.895 Å / Mean I/σ(I) obs: 0.68 / Num. unique obs: 2967 / CC1/2: 0.394

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.83→45.78 Å / SU ML: 0.2413 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 24.3851
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.225 1510 5 %
Rwork0.1951 28705 -
obs0.1966 30215 99.52 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 33.55 Å2
Refinement stepCycle: LAST / Resolution: 1.83→45.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2297 0 29 273 2599
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00552396
X-RAY DIFFRACTIONf_angle_d1.04613244
X-RAY DIFFRACTIONf_chiral_restr0.0613339
X-RAY DIFFRACTIONf_plane_restr0.0077416
X-RAY DIFFRACTIONf_dihedral_angle_d6.4436314
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.83-1.890.34091340.32712560X-RAY DIFFRACTION99.15
1.89-1.960.35341370.30392598X-RAY DIFFRACTION99.53
1.96-2.030.33271370.27692615X-RAY DIFFRACTION99.82
2.03-2.130.30061370.25752592X-RAY DIFFRACTION99.24
2.13-2.240.281370.23332605X-RAY DIFFRACTION99.6
2.24-2.380.23611360.20192586X-RAY DIFFRACTION99.82
2.38-2.560.22711380.1972620X-RAY DIFFRACTION99.96
2.56-2.820.2111370.19662609X-RAY DIFFRACTION99.75
2.82-3.230.21431380.18492620X-RAY DIFFRACTION99.24
3.23-4.070.18911380.16372621X-RAY DIFFRACTION99.6

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