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

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Basic information

Entry
Database: PDB / ID: 8cjj
TitleCrystal structure of human tryptophan hydroxylase 1 in complex with inhibitor KM-06-057
ComponentsTryptophan 5-hydroxylase 1Tryptophan hydroxylase
KeywordsMETAL BINDING PROTEIN / catalytic domain of human tryptophan hydroxylase 1 (TPH1) / inhibitor complex
Function / homology
Function and homology information


regulation of hemostasis / tryptophan 5-monooxygenase / tryptophan 5-monooxygenase activity / Serotonin and melatonin biosynthesis / serotonin biosynthetic process / aromatic amino acid metabolic 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 / serotonin biosynthetic process / aromatic amino acid metabolic 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 / 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-UVF / Tryptophan 5-hydroxylase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.66415657298 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)37,8853
Polymers37,4251
Non-polymers4602
Water4,774265
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 area13050 Å2
MethodPISA
Unit cell
Length a, b, c (Å)47.004, 58.042, 59.412
Angle α, β, γ (deg.)90.0, 97.928, 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 hydroxylase / 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 / Iron


Mass: 55.845 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Fe
#3: Chemical ChemComp-UVF / 3-ethyl-7-(phenylmethyl)-8-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-ylmethyl)purine-2,6-dione


Mass: 404.465 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H24N6O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 265 / 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: 2.14 Å3/Da / Density % sol: 42.65 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / Details: 20% PEG 5000 MME, 0.2 M lithium acetate

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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: Jan 26, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.664→46.55 Å / Num. obs: 37060 / % possible obs: 99.46 % / Redundancy: 4.5 % / Biso Wilson estimate: 18.9051202558 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.07553 / Net I/σ(I): 13.12
Reflection shellResolution: 1.664→1.724 Å / Rmerge(I) obs: 0.8066 / Mean I/σ(I) obs: 1.69 / Num. unique obs: 3585 / CC1/2: 0.692 / % possible all: 97.02

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.66415657298→46.55 Å / SU ML: 0.173840688813 / Cross valid method: FREE R-VALUE / σ(F): 1.36534139867 / Phase error: 20.1080123554
RfactorNum. reflection% reflection
Rfree0.203226343466 1853 5 %
Rwork0.175245155349 35207 -
obs0.176635054312 37060 99.4605619817 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 26.3932631618 Å2
Refinement stepCycle: LAST / Resolution: 1.66415657298→46.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2363 0 31 265 2659
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.009887938350242473
X-RAY DIFFRACTIONf_angle_d1.349412119523348
X-RAY DIFFRACTIONf_chiral_restr0.0609933571722348
X-RAY DIFFRACTIONf_plane_restr0.00758581270854431
X-RAY DIFFRACTIONf_dihedral_angle_d12.2277405535928
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6642-1.70920.2702397920821360.242634851392595X-RAY DIFFRACTION96.2976022567
1.7092-1.75940.2424799777091420.2257109485682697X-RAY DIFFRACTION99.5790950544
1.7594-1.81620.2394000621571430.2105064574052713X-RAY DIFFRACTION99.2355802641
1.8162-1.88120.2614645884751410.2116452550822688X-RAY DIFFRACTION99.507562434
1.8812-1.95650.2207935758931420.1904760157182683X-RAY DIFFRACTION99.6824276641
1.9565-2.04550.1934606255351420.1731037596842714X-RAY DIFFRACTION99.9300209937
2.0455-2.15340.2075449503291430.1680785260722710X-RAY DIFFRACTION99.9299474606
2.1534-2.28830.2048913469611430.1714478918182717X-RAY DIFFRACTION99.930118798
2.2883-2.46490.2168273459871430.1671456684652719X-RAY DIFFRACTION99.8256016742
2.4649-2.7130.2034025874141430.1743971090612713X-RAY DIFFRACTION99.8601398601
2.713-3.10550.1955149819071440.1710597548992738X-RAY DIFFRACTION99.9306518724
3.1055-3.91230.1868089283171440.1614882721042745X-RAY DIFFRACTION99.8272287491
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)
11.76474414301-0.672627481188-0.7945322745381.29804722170.4374138605150.541963982907-0.01686446258970.410347871508-0.137339543095-0.309032138071-0.04051349303020.1875469672710.0883208151517-0.1710308086370.07764284121430.215312254202-0.0317899000767-0.02561425433880.197404944097-0.01191712764640.202090849075-24.9978831445-0.901184615873-13.1945246291
22.997411711811.24612096042-0.1970970671354.48582413265-0.5354651422660.992941486926-0.08242320900980.0905921431105-0.46134416635-0.207681571365-0.0732916623196-0.8477599771710.1581069866890.1940783444740.1054031801590.170997951040.06041697446910.03229918488130.2021089374340.00505829192150.221381087831-0.825563015798-1.66891268392-11.4816260361
31.39689665092-0.341990941965-0.1585912450951.87670348114-0.3414338898860.8456402044440.02664688850020.0758797275347-0.00375116299678-0.0470123428457-0.016270051446-0.08684944327210.03064347810550.0938685768874-0.01771199298160.1098262407640.00226317061447-0.002510454498150.131356802364-0.01700303892280.0966844263672-13.27416426149.77169217807-9.34641739141
42.95867966587-1.37336310598-0.1503190132133.51742661956-0.02471449374942.33520787230.1902044124950.4532872788750.104796987154-0.380816694062-0.16166490395-0.0180734013246-0.1657427316290.0808909910376-0.04352288735460.1584157817040.001307953607630.01782500446590.2087864088780.02718634263410.139313869796-8.7928829340320.1723147503-19.1003258213
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 104 through 167 )
2X-RAY DIFFRACTION2chain 'A' and (resid 168 through 188 )
3X-RAY DIFFRACTION3chain 'A' and (resid 189 through 329 )
4X-RAY DIFFRACTION4chain 'A' and (resid 330 through 394 )

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