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- PDB-5j6d: Discovery of acyl guanidine tryptophan hydroxylase-1 inhibitors -

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Basic information

Entry
Database: PDB / ID: 5j6d
TitleDiscovery of acyl guanidine tryptophan hydroxylase-1 inhibitors
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 / 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 / positive regulation of fat cell differentiation / mammary gland alveolus development / circadian rhythm / 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-6H5 / : / 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.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2016
Title: Discovery of acyl guanidine tryptophan hydroxylase-1 inhibitors.
Authors: Goldberg, D.R. / De Lombaert, S. / Aiello, R. / Bourassa, P. / Barucci, N. / Zhang, Q. / Paralkar, V. / Stein, A.J. / Valentine, J. / Zavadoski, W.
History
DepositionApr 4, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 25, 2016Provider: repository / Type: Initial release
Revision 1.1Jun 15, 2016Group: Database references
Revision 1.2Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / pdbx_initial_refinement_model / pdbx_struct_oper_list / struct_conn
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tryptophan 5-hydroxylase 1
B: Tryptophan 5-hydroxylase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,54210
Polymers70,9112
Non-polymers1,6318
Water2,522140
1
A: Tryptophan 5-hydroxylase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,2715
Polymers35,4551
Non-polymers8164
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tryptophan 5-hydroxylase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,2715
Polymers35,4551
Non-polymers8164
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4130 Å2
ΔGint-43 kcal/mol
Surface area21410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.726, 63.561, 156.468
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 35455.348 Da / Num. of mol.: 2 / Fragment: UNP residues 102-402
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TPH1, TPH, TPRH, TRPH / Plasmid: pET21 / Production host: Escherichia coli (E. coli) / References: UniProt: P17752, tryptophan 5-monooxygenase

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Non-polymers , 5 types, 148 molecules

#2: Chemical ChemComp-FE / FE (III) ION


Mass: 55.845 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Fe
#3: Chemical ChemComp-TRS / 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / TRIS BUFFER


Mass: 122.143 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H12NO3 / Comment: pH buffer*YM
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-6H5 / 4-[(N-{[2-(3-methoxyphenoxy)-6-(piperidin-1-yl)phenyl]methyl}carbamimidoyl)carbamoyl]-L-phenylalanine


Mass: 545.629 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H35N5O5
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 140 / 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: 2.04 Å3/Da / Density % sol: 39.76 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.4 / Details: 20% PEG 3350, CBTP pH 8.4, 2.5 mM TCEP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Oct 22, 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: 47119 / % possible obs: 100 % / Redundancy: 3.4 % / Rmerge(I) obs: 0.077 / Net I/σ(I): 23.5
Reflection shellResolution: 1.9→1.97 Å / Rmerge(I) obs: 0.796

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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: 3HF8

3hf8


Resolution: 1.9→50 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.934 / SU B: 4.111 / SU ML: 0.118 / Cross valid method: THROUGHOUT / ESU R: 0.161 / ESU R Free: 0.149 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24812 2245 4.8 %RANDOM
Rwork0.20984 ---
obs0.21172 44777 99.94 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 46.064 Å2
Baniso -1Baniso -2Baniso -3
1-0.01 Å20 Å20 Å2
2---0 Å20 Å2
3----0.01 Å2
Refinement stepCycle: LAST / Resolution: 1.9→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4074 0 110 140 4324
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0194305
X-RAY DIFFRACTIONr_bond_other_d0.0020.023852
X-RAY DIFFRACTIONr_angle_refined_deg1.4611.9835848
X-RAY DIFFRACTIONr_angle_other_deg1.00138830
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.6925534
X-RAY DIFFRACTIONr_dihedral_angle_2_deg29.51923.353173
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.37915608
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.8571518
X-RAY DIFFRACTIONr_chiral_restr0.10.2642
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0214857
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021015
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_it2.4974.9882156
X-RAY DIFFRACTIONr_mcbond_other2.4974.9872153
X-RAY DIFFRACTIONr_mcangle_it3.7667.4472676
X-RAY DIFFRACTIONr_mcangle_other3.7657.4492677
X-RAY DIFFRACTIONr_scbond_it2.6014.8262149
X-RAY DIFFRACTIONr_scbond_other2.6014.8272150
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.9027.2473171
X-RAY DIFFRACTIONr_long_range_B_refined5.83738.7064875
X-RAY DIFFRACTIONr_long_range_B_other5.77238.7354816
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.9→1.949 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.289 161 -
Rwork0.291 3238 -
obs--99.77 %

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