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

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Basic information

Entry
Database: PDB / ID: 8cjn
TitleCrystal structure of human tryptophan hydroxylase 1 in complex with inhibitor KM-06-070
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 / bone remodeling / NGF-stimulated transcription / negative regulation of ossification ...regulation of hemostasis / tryptophan 5-monooxygenase / tryptophan 5-monooxygenase activity / Serotonin and melatonin biosynthesis / aromatic amino acid metabolic process / serotonin biosynthetic process / platelet degranulation / bone remodeling / NGF-stimulated transcription / negative regulation of ossification / response to immobilization stress / mammary gland alveolus development / positive regulation of fat cell differentiation / circadian rhythm / 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-UX3 / Tryptophan 5-hydroxylase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6808093833 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)37,9613
Polymers37,4251
Non-polymers5362
Water5,441302
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 area12820 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.884, 58.018, 59.115
Angle α, β, γ (deg.)90.0, 98.047, 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
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-UX3 / 3-ethyl-7-[(4-phenylphenyl)methyl]-8-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-ylmethyl)purine-2,6-dione


Mass: 480.561 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H28N6O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 302 / 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: 2.13 Å3/Da / Density % sol: 42.18 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / Details: 20% PEG3350, 0.2 M NaF

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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: Mar 2, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.6808093833→39.14 Å / Num. obs: 35715 / % possible obs: 99.57 % / Redundancy: 3.9 % / Biso Wilson estimate: 17.9655473535 Å2 / CC1/2: 0.998 / Net I/σ(I): 13.89
Reflection shellResolution: 1.681→1.741 Å / Mean I/σ(I) obs: 1.77 / Num. unique obs: 3470 / CC1/2: 0.652

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.6808093833→39.1368862602 Å / SU ML: 0.169388706895 / Cross valid method: FREE R-VALUE / σ(F): 1.35887296424 / Phase error: 19.8572110561
RfactorNum. reflection% reflection
Rfree0.197210123888 1786 5.00098003528 %
Rwork0.165640890825 33927 -
obs0.167222768074 35713 99.5706359606 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 23.7949368912 Å2
Refinement stepCycle: LAST / Resolution: 1.6808093833→39.1368862602 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2352 0 37 302 2691
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.005358542506192469
X-RAY DIFFRACTIONf_angle_d1.20134022613344
X-RAY DIFFRACTIONf_chiral_restr0.0507000613288347
X-RAY DIFFRACTIONf_plane_restr0.00547468300571430
X-RAY DIFFRACTIONf_dihedral_angle_d11.243631192924
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6808093833-1.72630.2817240143521320.2604484404472505X-RAY DIFFRACTION96.6642228739
1.7263-1.77710.2571807817421360.2305284994132594X-RAY DIFFRACTION99.6714129244
1.7771-1.83440.2518366649081370.214467141152599X-RAY DIFFRACTION99.5271007639
1.8344-1.90.2645479842751370.2073818326852600X-RAY DIFFRACTION99.7812613926
1.9-1.9760.2168168041391370.1904195450562608X-RAY DIFFRACTION99.8908296943
1.976-2.0660.229946524231380.1730988292732621X-RAY DIFFRACTION99.9275624774
2.066-2.17490.2053089959651370.1692160436772593X-RAY DIFFRACTION99.8171846435
2.1749-2.31110.2110441217251370.1634062222812610X-RAY DIFFRACTION99.9272462714
2.3111-2.48950.1969296235031380.1624464385812629X-RAY DIFFRACTION99.9638728324
2.4895-2.740.1980663280441380.1662564378792614X-RAY DIFFRACTION100
2.74-3.13640.1829627340721380.1641490369362630X-RAY DIFFRACTION99.9277978339
3.1364-3.95090.1682790930691400.1459500716292651X-RAY DIFFRACTION99.7854844476

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