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

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Basic information

Entry
Database: PDB / ID: 7zij
TitleCrystal structure of human tryptophan hydroxylase 1 in complex with inhibitor KM-05-080
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-IVW / Tryptophan 5-hydroxylase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.94678362883 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

Downloads & links

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Assembly

Deposited unit
A: Tryptophan 5-hydroxylase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,8933
Polymers37,4251
Non-polymers4682
Water3,441191
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 area12830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)47.05, 57.65, 69.481
Angle α, β, γ (deg.)90.0, 109.714, 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-IVW / 8-(1~{H}-benzimidazol-2-ylmethyl)-3-cyclopropyl-7-(phenylmethyl)purine-2,6-dione


Mass: 412.444 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H20N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-FE / FE (III) ION


Mass: 55.845 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Fe
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 191 / 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: 2.37 Å3/Da / Density % sol: 48.07 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / Details: 20% w/v PEG 5000 MME, 200 mM ammonium fluoride

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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 20, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.94678362883→47.05 Å / Num. obs: 25548 / % possible obs: 98.89 % / Redundancy: 3.6 % / Biso Wilson estimate: 25.8248919038 Å2 / Rmerge(I) obs: 0.0805 / Net I/σ(I): 10.41
Reflection shellResolution: 1.95→2.02 Å / Rmerge(I) obs: 0.6077 / Num. unique obs: 2405

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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: 1.94678362883→44.2923124009 Å / SU ML: 0.219861246828 / Cross valid method: FREE R-VALUE / σ(F): 1.3625350587 / Phase error: 26.9285057102
RfactorNum. reflection% reflection
Rfree0.225544799513 1278 5.0029359953 %
Rwork0.186253646429 24267 -
obs0.188234943903 25545 98.8774917747 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 35.6474442556 Å2
Refinement stepCycle: LAST / Resolution: 1.94678362883→44.2923124009 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2305 0 32 191 2528
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01030762470752413
X-RAY DIFFRACTIONf_angle_d1.226635724153266
X-RAY DIFFRACTIONf_chiral_restr0.0685143485007341
X-RAY DIFFRACTIONf_plane_restr0.00724131451124419
X-RAY DIFFRACTIONf_dihedral_angle_d11.3423367903897
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9468-2.02470.3321949146371340.2999197581822542X-RAY DIFFRACTION94.6586487443
2.0247-2.11690.2804869275621450.2609427660192746X-RAY DIFFRACTION99.5523415978
2.1169-2.22850.2931365536791400.2336013404632665X-RAY DIFFRACTION99.2920353982
2.2285-2.36810.2677463312361390.2155480342372653X-RAY DIFFRACTION98.5527709142
2.3681-2.55090.2739990744811440.1981426132842728X-RAY DIFFRACTION99.7222222222
2.5509-2.80760.2343589169721420.2030753870082703X-RAY DIFFRACTION99.4407549808
2.8076-3.21370.2329368629121440.1842772778242739X-RAY DIFFRACTION99.8614478698
3.2137-4.04860.2019652897791430.1571915959172709X-RAY DIFFRACTION99.338209683

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