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- PDB-9hb8: Crystal structure of human tryptophan hydroxylase 2 in complex wi... -

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Basic information

Entry
Database: PDB / ID: 9hb8
TitleCrystal structure of human tryptophan hydroxylase 2 in complex with inhibitor KM-06-098
ComponentsTryptophan 5-hydroxylase 2
KeywordsMETAL BINDING PROTEIN / catalytic and oligomerization domain / TPH2 / inhibitor
Function / homology
Function and homology information


tryptophan 5-monooxygenase / tryptophan 5-monooxygenase activity / Serotonin and melatonin biosynthesis / aromatic amino acid metabolic process / serotonin biosynthetic process / 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-UVU / Tryptophan 5-hydroxylase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.89634214817 Å
AuthorsSchuetz, A. / Mallow, K. / Nazare, M. / Specker, E. / Heinemann, U.
Funding support Germany, 1items
OrganizationGrant numberCountry
Helmholtz Association Germany
CitationJournal: Acs Pharmacol Transl Sci / Year: 2025
Title: Selectivity and Safety Characterization of a Xanthine-Imidazothiazole Lead Structure: a Novel Tryptophan Hydroxylase Inhibitor of Peripheral Serotonin Synthesis.
Authors: Wesolowski, R. / Schutz, A. / Lisurek, M. / Nazare, M. / Heinemann, U. / Pleimes, D. / Bader, M. / Specker, E.
History
DepositionNov 5, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 16, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tryptophan 5-hydroxylase 2
B: Tryptophan 5-hydroxylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)86,6246
Polymers85,5112
Non-polymers1,1134
Water362
1
A: Tryptophan 5-hydroxylase 2
B: Tryptophan 5-hydroxylase 2
hetero molecules

A: Tryptophan 5-hydroxylase 2
B: Tryptophan 5-hydroxylase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)173,24812
Polymers171,0224
Non-polymers2,2268
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_755-x+2,-y,z1
Buried area13460 Å2
ΔGint-54 kcal/mol
Surface area54340 Å2
Unit cell
Length a, b, c (Å)100.507, 94.11, 87.922
Angle α, β, γ (deg.)90.0, 90.0, 90.0
Int Tables number18
Space group name H-MP21212
Space group name HallP22ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x+1/2,y+1/2,-z
#4: -x,-y,z
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
21

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11GLUGLUTYRTYRchain 'A'AA149 - 17131 - 53
12GLUGLUPROPROchain 'A'AA174 - 18056 - 62
13ASPASPHISHISchain 'A'AA184 - 30466 - 186
14SERSERASPASPchain 'A'AA306 - 393188 - 275
15CYSCYSGLUGLUchain 'A'AA396 - 417278 - 299
16TYRTYRILEILEchain 'A'AA419 - 490301 - 372
27GLUGLUTYRTYRchain 'B'BB149 - 17131 - 53
28GLUGLUPROPROchain 'B'BB174 - 18056 - 62
29ASPASPHISHISchain 'B'BB184 - 30466 - 186
210SERSERASPASPchain 'B'BB306 - 393188 - 275
211CYSCYSGLUGLUchain 'B'BB396 - 417278 - 299
212TYRTYRILEILEchain 'B'BB419 - 490301 - 372

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Components

#1: Protein Tryptophan 5-hydroxylase 2 / Neuronal tryptophan hydroxylase / Tryptophan 5-monooxygenase 2


Mass: 42755.473 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TPH2, NTPH / Production host: Escherichia coli B (bacteria) / References: UniProt: Q8IWU9, tryptophan 5-monooxygenase
#2: Chemical ChemComp-FE / FE (III) ION


Mass: 55.845 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Fe
#3: Chemical ChemComp-UVU / 3-ethyl-8-[(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)methyl]-7-[[4-(1-methylpyrazol-3-yl)phenyl]methyl]purine-2,6-dione


Mass: 500.575 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H24N8O2S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.43 Å3/Da / Density % sol: 49.41 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 17.5% w/v PEG 3350, 200 mM sodium acetate, 0.1 M BisTrisPropane pH 7.0, 10% v/v ethylene glycol

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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: May 19, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 2.896→47.05 Å / Num. obs: 19065 / % possible obs: 99.47 % / Redundancy: 6.2 % / Biso Wilson estimate: 87.4835672759 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.09037 / Net I/σ(I): 15.54
Reflection shellResolution: 2.9→3 Å / Rmerge(I) obs: 1.507 / Num. unique obs: 1849 / CC1/2: 0.487

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.89634214817→47.05 Å / SU ML: 0.438124972899 / Cross valid method: FREE R-VALUE / σ(F): 1.36330507822 / Phase error: 27.2668100878
RfactorNum. reflection% reflection
Rfree0.24861662521 953 5.00052471403 %
Rwork0.209303835717 18105 -
obs0.211228990568 19058 99.4365021392 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 106.714907766 Å2
Refinement stepCycle: LAST / Resolution: 2.89634214817→47.05 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5489 0 74 2 5565
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.005417370993145705
X-RAY DIFFRACTIONf_angle_d1.145047305617725
X-RAY DIFFRACTIONf_chiral_restr0.0455535309958814
X-RAY DIFFRACTIONf_plane_restr0.00832896406718992
X-RAY DIFFRACTIONf_dihedral_angle_d11.70498651062126
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.89634214817-3.0490.3547541389791330.3421589932572529X-RAY DIFFRACTION98.3739837398
3.049-3.240.3366325916171340.2929040817582539X-RAY DIFFRACTION99.8878923767
3.24-3.49010.3315588276231350.2582042927632568X-RAY DIFFRACTION99.889135255
3.4901-3.84120.2636338051031350.21865812432564X-RAY DIFFRACTION99.5206489676
3.8412-4.39660.23796934981360.1901314902622576X-RAY DIFFRACTION99.852724595
4.3966-5.53790.2170324877561370.1907341163132614X-RAY DIFFRACTION99.6017378711
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.890776186531.185202507462.542579093191.714142480141.076220526833.289899001150.32188121723-0.271907659789-0.165081950010.392804621341-0.0593396139539-0.2465668866220.294160809168-0.122359646441-0.2613277572850.473694458986-0.03794562311820.006413141527150.471396386198-0.01146865322310.624115862935122.3190831376.417598821442.23609463946
23.41435471124-0.0600950734092-1.353143030622.38655519549-0.6699581328463.152477555770.1382448032860.5180317106750.355082422644-0.948503010274-0.207864500087-0.593692787252-0.2423543615690.5334285467220.0746910539050.852840514467-0.0121290505760.1523950287180.7277869107790.07884871053210.731092879569123.4117847657.23360496514-33.5658690388
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A'
2X-RAY DIFFRACTION2chain 'B'

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