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

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Basic information

Entry
Database: PDB / ID: 7zig
TitleCrystal structure of human tryptophan hydroxylase 1 in complex with inhibitor KM-05-060
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-IVZ / Tryptophan 5-hydroxylase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.80888497598 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)38,0113
Polymers37,4251
Non-polymers5862
Water4,107228
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 area12940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)47.411, 57.899, 59.387
Angle α, β, γ (deg.)90.0, 98.128, 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-IVZ / (2~{R})-2-azanyl-5-[[2-[[3-methyl-2,6-bis(oxidanylidene)-7-(phenylmethyl)purin-8-yl]methyl]-1~{H}-benzimidazol-5-yl]amino]-5-oxidanylidene-pentanoic acid


Mass: 530.535 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H26N8O5 / 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.: 228 / 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: 2.15 Å3/Da / Density % sol: 42.91 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop
Details: 26% w/v PEG 5000 MME, 200 mM ammonium sulfate, 100 mM Hepes-NaOH pH 7.0

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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 23, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.80888497598→46.94 Å / Num. obs: 29078 / % possible obs: 99.55 % / Redundancy: 3.4 % / Biso Wilson estimate: 20.6670291209 Å2 / Rmerge(I) obs: 0.077 / Net I/σ(I): 11.23
Reflection shellResolution: 1.81→1.87 Å / Rmerge(I) obs: 0.6311 / Num. unique obs: 2828

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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: 1.80888497598→46.9347414363 Å / SU ML: 0.200614705703 / Cross valid method: FREE R-VALUE / σ(F): 1.36346996767 / Phase error: 21.1882853641
RfactorNum. reflection% reflection
Rfree0.206340566536 1454 5.00051587165 %
Rwork0.167897277025 27623 -
obs0.16980701173 29077 99.5514927417 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 27.1641098215 Å2
Refinement stepCycle: LAST / Resolution: 1.80888497598→46.9347414363 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2305 0 40 228 2573
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01384751013822425
X-RAY DIFFRACTIONf_angle_d1.518440597853285
X-RAY DIFFRACTIONf_chiral_restr0.0806750218617342
X-RAY DIFFRACTIONf_plane_restr0.00998392858274424
X-RAY DIFFRACTIONf_dihedral_angle_d12.0662497661908
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8089-1.87350.2982948574221410.2406359740942687X-RAY DIFFRACTION98.1603609858
1.8735-1.94860.2609384785951450.2232615317622747X-RAY DIFFRACTION99.6210816397
1.9486-2.03720.2722579224461440.2069175658962733X-RAY DIFFRACTION99.7227036395
2.0372-2.14460.2555246467061460.1938570636182777X-RAY DIFFRACTION99.8633413051
2.1446-2.2790.2454062833031460.1744349646772776X-RAY DIFFRACTION99.8291766314
2.279-2.4550.1879126432661440.1676999153662747X-RAY DIFFRACTION99.7584541063
2.455-2.7020.2097114428391460.1711027487732776X-RAY DIFFRACTION99.7610105838
2.702-3.09290.1939767273531460.1715232907032760X-RAY DIFFRACTION99.6570644719
3.0929-3.89650.1922038026091460.1510675059942788X-RAY DIFFRACTION99.7619857191

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