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- PDB-5l01: Tryptophan 5-hydroxylase in complex with inhibitor (3~{S})-8-[2-a... -

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Basic information

Entry
Database: PDB / ID: 5l01
TitleTryptophan 5-hydroxylase in complex with inhibitor (3~{S})-8-[2-azanyl-6-[(1~{R})-1-(4-chloranyl-2-phenyl-phenyl)-2,2,2-tris(fluoranyl)ethoxy]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-3-carboxylic acid
ComponentsTryptophan 5-hydroxylase 1
KeywordsOXIDOREDUCTASE/INHIBITOR / TPH1 / Iron / acyl / quanidine / OXIDOREDUCTASE-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 / 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 / bone remodeling / NGF-stimulated transcription / 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 / Phenylalanine Hydroxylase / Aromatic amino acid hydroxylase / 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 ...Tryptophan 5-monooxygenase / Tryptophan 5-hydroxylase, catalytic domain / Phenylalanine Hydroxylase / Aromatic amino acid hydroxylase / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-6Z4 / : / Tryptophan 5-hydroxylase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsStein, A.J. / Goldberg, D.R. / De Lombaert, S. / Holt, M.C.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2017
Title: Optimization of spirocyclic proline tryptophan hydroxylase-1 inhibitors.
Authors: Goldberg, D.R. / De Lombaert, S. / Aiello, R. / Bourassa, P. / Barucci, N. / Zhang, Q. / Paralkar, V. / Stein, A.J. / Holt, M. / Valentine, J. / Zavadoski, W.
History
DepositionJul 26, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 25, 2017Provider: repository / Type: Initial release
Revision 1.1Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)51,6793
Polymers51,0611
Non-polymers6182
Water2,540141
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area140 Å2
ΔGint-14 kcal/mol
Surface area12380 Å2
MethodPISA
Unit cell
Length a, b, c (Å)47.302, 58.167, 56.678
Angle α, β, γ (deg.)90.00, 97.49, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Tryptophan 5-hydroxylase 1 / Tryptophan 5-monooxygenase 1


Mass: 51061.117 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 K-12 (bacteria) / Strain (production host): K-12 / 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-6Z4 / (3~{S})-8-[2-azanyl-6-[(1~{R})-1-(4-chloranyl-2-phenyl-phenyl)-2,2,2-tris(fluoranyl)ethoxy]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-3-carboxylic acid


Mass: 561.983 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H27ClF3N5O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 141 / Source method: isolated from a natural source / Formula: H2O

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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: 1.51 Å3/Da / Density % sol: 18.76 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.6
Details: 20% PEG 3350, 0.05M citrate/0.05 M Bis-tris Propane pH 7.6, 5% PEG 400

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 1 Å
DetectorType: RAYONIX MX-225 / Detector: CCD / Date: Aug 14, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. obs: 24161 / % possible obs: 100 % / Redundancy: 3.8 % / Net I/σ(I): 12.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5J6D

5j6d


Resolution: 1.9→38.56 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.939 / SU B: 3.688 / SU ML: 0.105 / Cross valid method: THROUGHOUT / ESU R: 0.142 / ESU R Free: 0.136 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21421 1232 5.1 %RANDOM
Rwork0.16925 ---
obs0.17153 22904 99.87 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 25.226 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å2-0.01 Å2
2--0 Å20 Å2
3----0.01 Å2
Refinement stepCycle: LAST / Resolution: 1.9→38.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2254 0 40 141 2435
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0192388
X-RAY DIFFRACTIONr_bond_other_d0.0030.022206
X-RAY DIFFRACTIONr_angle_refined_deg1.9761.9863242
X-RAY DIFFRACTIONr_angle_other_deg1.083.0095093
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1345289
X-RAY DIFFRACTIONr_dihedral_angle_2_deg27.96123.182110
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.71715392
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.4231515
X-RAY DIFFRACTIONr_chiral_restr0.1180.2341
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0212667
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02572
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.062.2951141
X-RAY DIFFRACTIONr_mcbond_other2.0612.2961140
X-RAY DIFFRACTIONr_mcangle_it2.9263.4241423
X-RAY DIFFRACTIONr_mcangle_other2.9253.4241424
X-RAY DIFFRACTIONr_scbond_it3.3682.6711247
X-RAY DIFFRACTIONr_scbond_other3.3672.6711248
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.1973.8561816
X-RAY DIFFRACTIONr_long_range_B_refined6.51219.0762804
X-RAY DIFFRACTIONr_long_range_B_other6.51119.0822805
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.901→1.95 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.294 87 -
Rwork0.262 1682 -
obs--98.55 %

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