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

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Basic information

Entry
Database: PDB / ID: 8cji
TitleCrystal structure of human tryptophan hydroxylase 1 in complex with inhibitor KM-07-052
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-UWC / Tryptophan 5-hydroxylase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.65 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)38,0293
Polymers37,4251
Non-polymers6042
Water5,152286
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area12790 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.840, 57.700, 58.800
Angle α, β, γ (deg.)90.000, 97.660, 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
#3: Chemical ChemComp-UWC / methyl (2~{S})-2-azanyl-3-[[3-[[3-ethyl-2,6-bis(oxidanylidene)-8-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-ylmethyl)purin-7-yl]methyl]phenyl]carbonylamino]propanoate


Mass: 548.594 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H32N8O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 286 / 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: 2.1 Å3/Da / Density % sol: 41.55 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / Details: 21% PEG3350, 0.2 M NaCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.2 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Apr 4, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.65→41 Å / Num. obs: 37090 / % possible obs: 98.91 % / Redundancy: 5 % / Biso Wilson estimate: 22.41 Å2 / CC1/2: 0.998 / Net I/σ(I): 11.43
Reflection shellResolution: 1.65→1.709 Å / Mean I/σ(I) obs: 1.07 / Num. unique obs: 3621 / CC1/2: 0.403

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.65→41 Å / SU ML: 0.244 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 29.6444
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2652 1855 5 %
Rwork0.2365 35235 -
obs0.2379 37090 98.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 28.94 Å2
Refinement stepCycle: LAST / Resolution: 1.65→41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2343 0 41 286 2670
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00482456
X-RAY DIFFRACTIONf_angle_d0.7753326
X-RAY DIFFRACTIONf_chiral_restr0.0482346
X-RAY DIFFRACTIONf_plane_restr0.0061428
X-RAY DIFFRACTIONf_dihedral_angle_d12.5231927
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.65-1.690.34551390.34712644X-RAY DIFFRACTION98.24
1.69-1.740.33931430.32352727X-RAY DIFFRACTION99.65
1.74-1.80.30441450.29182738X-RAY DIFFRACTION99.83
1.8-1.860.3241420.28662703X-RAY DIFFRACTION99.82
1.86-1.940.32231420.27362699X-RAY DIFFRACTION99.61
1.94-2.030.3041430.25052711X-RAY DIFFRACTION98.69
2.03-2.130.30231410.24512692X-RAY DIFFRACTION98.5
2.13-2.270.30851410.24542670X-RAY DIFFRACTION97.5
2.27-2.440.26271400.24142659X-RAY DIFFRACTION97.29
2.44-2.690.24741440.24512738X-RAY DIFFRACTION99.79
2.69-3.080.26881450.2352750X-RAY DIFFRACTION99.48
3.08-3.880.26161430.21262728X-RAY DIFFRACTION98.93
3.88-410.2121470.20832776X-RAY DIFFRACTION98.45

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