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- PDB-8cjk: Crystal structure of human tryptophan hydroxylase 1 in complex wi... -

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Basic information

Entry
Database: PDB / ID: 8cjk
TitleCrystal structure of human tryptophan hydroxylase 1 in complex with inhibitor KM-06-098
ComponentsTryptophan 5-hydroxylase 1
KeywordsMETAL BINDING PROTEIN / catalytic domain / TPH1 / inhibitor
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 / mammary gland alveolus development / positive regulation of fat cell differentiation / circadian rhythm / 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 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.45914977372 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: 2023
Title: Structure-Based Design of Xanthine-Imidazopyridines and -Imidazothiazoles as Highly Potent and In Vivo Efficacious Tryptophan Hydroxylase Inhibitors.
Authors: Specker, E. / Wesolowski, R. / Schutz, A. / Matthes, S. / Mallow, K. / Wasinska-Kalwa, M. / Winkler, L. / Oder, A. / Alenina, N. / Pleimes, D. / von Kries, J.P. / Heinemann, U. / Bader, M. / Nazare, M.
History
DepositionFeb 13, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 10, 2024Provider: 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 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,9813
Polymers37,4251
Non-polymers5562
Water6,377354
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area140 Å2
ΔGint-14 kcal/mol
Surface area12830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.96, 57.875, 59.054
Angle α, β, γ (deg.)90.0, 97.741, 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-FE / FE (III) ION


Mass: 55.845 Da / Num. of mol.: 1 / 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.: 1 / Source method: obtained synthetically / Formula: C25H24N8O2S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 354 / 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: 2.38 Å3/Da / Density % sol: 48.35 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / Details: 27% PEG 3350, 0.2 M NaCl

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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 12, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.459→41.15 Å / Num. obs: 54099 / % possible obs: 99.05 % / Redundancy: 3.7 % / Biso Wilson estimate: 15.8717395253 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.06335 / Net I/σ(I): 13.36
Reflection shellResolution: 1.459→1.511 Å / Rmerge(I) obs: 0.8468 / Mean I/σ(I) obs: 1.58 / Num. unique obs: 5279 / CC1/2: 0.622 / % possible all: 96.63

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.45914977372→41.1485066195 Å / SU ML: 0.146143453055 / Cross valid method: FREE R-VALUE / σ(F): 1.36700110579 / Phase error: 18.782577142
RfactorNum. reflection% reflection
Rfree0.183981915097 2101 3.88376434922 %
Rwork0.154573739291 51996 -
obs0.155720294446 54097 99.0442886175 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 24.6504132848 Å2
Refinement stepCycle: LAST / Resolution: 1.45914977372→41.1485066195 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2352 0 37 354 2743
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.009993464596822462
X-RAY DIFFRACTIONf_angle_d1.288941275933335
X-RAY DIFFRACTIONf_chiral_restr0.0522417399846346
X-RAY DIFFRACTIONf_plane_restr0.00714107447474428
X-RAY DIFFRACTIONf_dihedral_angle_d11.7700890791914
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.45914977372-1.49310.2849553120941340.2843258451773312X-RAY DIFFRACTION95.1670809169
1.4931-1.53040.271839383541400.2431910288673471X-RAY DIFFRACTION99.6137931034
1.5304-1.57180.2763573270231400.2244354453773462X-RAY DIFFRACTION99.6679579413
1.5718-1.61810.2469621264941410.2067928613853476X-RAY DIFFRACTION99.231824417
1.6181-1.67030.2346670752351370.2020890245353405X-RAY DIFFRACTION98.883305416
1.6703-1.730.2021236882411390.1975855018783447X-RAY DIFFRACTION98.0317113177
1.73-1.79930.2289105823221400.1764894891543463X-RAY DIFFRACTION99.6680497925
1.7993-1.88110.2006437381321410.1610107180663491X-RAY DIFFRACTION99.7254255903
1.8811-1.98030.1860606448461410.1515832118473483X-RAY DIFFRACTION99.6699669967
1.9803-2.10440.1784211218371390.1472400491383445X-RAY DIFFRACTION99.1973429283
2.1044-2.26690.1868185368261400.1481773602743473X-RAY DIFFRACTION98.8508891929
2.2669-2.4950.17481610021420.1411591929073499X-RAY DIFFRACTION99.8081140351
2.495-2.85590.1575920098621410.1469408185323493X-RAY DIFFRACTION99.5889284736
2.8559-3.59780.1459546052441420.1438198438753511X-RAY DIFFRACTION99.3202827624
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)
11.29574271562-2.612051921992.378404815215.36503862085-4.699694930244.844206801870.01152394729960.2631730340620.139387864445-0.2054578989290.1572836633080.4167550838080.0278979227532-0.120523928425-0.1937223417150.138890832424-0.00853574490691-0.03205139651240.1780756141270.05175333435460.246396915007-33.828187510313.8431967181-7.99985171626
21.70512879235-2.05534841642-1.240694244554.455956864982.628231715592.62860817157-0.08025044289070.319627070757-0.267831144284-0.0259911628917-0.104185805170.376878840654-0.0402550950118-0.3370501349060.08627105312070.255983223032-0.00955608802337-0.05651679079180.295303824527-0.03324751898850.215330263505-22.3158932149-2.74536522243-22.8576453827
31.93293065042-1.23035820974-1.378724578521.747233096961.006828043812.31397838594-0.09953538724330.182595077865-0.2409248730520.0159376625584-0.0240891529190.1862819328970.218436825596-0.1935642174540.1090523500630.162598034578-0.0314629193718-0.02642517699220.112442065028-0.007738729489140.172899464929-22.2902810139-6.7661754586-9.76199281965
42.838694347411.87723254280.008614283417823.63687606035-0.02712946460221.03526702647-0.04199832812680.0284538722225-0.264534984143-0.152060666462-0.0786337146056-0.5996129794890.0877184429090.1602130383430.1073842678180.1371549957390.0464747995474-0.02770024357770.163040914020.0151086912580.207905038015-0.806841570996-1.6113633394-11.4653398476
50.8778851203371.51766704642-1.091153595015.70548740934-4.669374947236.850485716290.0258791842535-0.3472330027670.05827842805330.576996363151-0.101933417201-0.118716472399-0.3237455037970.1091861369460.1071659996480.18285006077-0.0118593396139-0.06783255863820.241187899329-0.006313093402620.216420309028-2.516319231859.73408083668-1.10067069302
63.56241174902-1.77453744067-1.384840575054.222923176030.9788097720433.21199117199-0.131425336646-0.233779871206-0.1911294306830.3745853955890.0515207967685-0.1140984749080.1792579983090.2549580647570.05339564579350.1382381069210.011003674805-0.05735824204710.1427994303530.01868625906770.124259658055-11.02404893571.575764669890.198609196614
71.07207662959-0.2820199689370.09391234146291.953732066620.1859717796570.6641198567140.06401589834690.1678891165460.0312687800013-0.0746345612777-0.0438488632683-0.08022434151290.07268548294240.0220089973306-0.009821852138640.1247358920531.35542632054E-5-0.02847560848070.125235461033-0.0008638625426550.106245169684-16.22893051495.48847958278-12.0164507782
81.56979345201-0.206645418777-0.8329374327411.594001365450.4016602334051.508857892950.07702383094270.2623983894170.14959201994-0.0931807711744-0.02781262999730.0660857514848-0.081342038614-0.0404948250429-0.06745632390810.1161875840050.0123032325035-0.02300177337330.09910020994310.0256555775780.118108188304-19.807599042920.2108873973-13.542386551
92.231002942870.32351639087-0.325508335212.652537004560.3101092244881.904360030240.1143578707430.1065672265630.05780617496420.0767766744152-0.0705042546779-0.496861199357-0.08925811104670.270699309333-0.02594493249960.111509925577-0.0132889898934-0.04034238468450.1593442693450.0200408964530.182914069486-2.6944934543816.1061571835-13.8340020578
102.35203227775-1.223029170160.4664380899183.17011008369-0.530309251621.26068983110.1772562087850.5060667368080.227396157915-0.367969201511-0.192451838267-0.185376867623-0.09094700415030.153819944824-0.05009642277970.1860329055020.01298016446550.02966753137810.2530379376620.05378873911450.177845442554-4.3556961234319.192435973-22.4242811125
111.82618212098-0.453860852596-1.117186409223.446991480741.461560217443.832791211960.02808337766180.5089817701250.0588425144582-0.49528348593-0.0450561047127-0.03341971760350.06387634855740.122909767259-0.04023376823830.2044174640480.0555002411003-0.004486855547460.2206534453730.03288292510720.136477546877-8.0876476673616.8944695075-23.6558895694
124.16387653568-1.286675994540.6365405403694.90213924590.5868200681353.66129665336-0.02075498795990.09092421494430.419574034987-0.1264234924040.00646848129396-0.00649752843485-0.61418371226-0.1390225860760.04957842595070.2462073632820.03394089494470.0228222575630.1180721831860.02740692393160.169414779198-16.417735745928.829781288-11.6691518873
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 104 through 118 )
2X-RAY DIFFRACTION2chain 'A' and (resid 119 through 138 )
3X-RAY DIFFRACTION3chain 'A' and (resid 139 through 167 )
4X-RAY DIFFRACTION4chain 'A' and (resid 168 through 188 )
5X-RAY DIFFRACTION5chain 'A' and (resid 189 through 203 )
6X-RAY DIFFRACTION6chain 'A' and (resid 204 through 225 )
7X-RAY DIFFRACTION7chain 'A' and (resid 226 through 283 )
8X-RAY DIFFRACTION8chain 'A' and (resid 284 through 315 )
9X-RAY DIFFRACTION9chain 'A' and (resid 316 through 337 )
10X-RAY DIFFRACTION10chain 'A' and (resid 338 through 361 )
11X-RAY DIFFRACTION11chain 'A' and (resid 362 through 378 )
12X-RAY DIFFRACTION12chain 'A' and (resid 379 through 394 )

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