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- PDB-4xud: Synthesis and evaluation of heterocyclic catechol mimics as inhib... -

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Basic information

Entry
Database: PDB / ID: 4xud
TitleSynthesis and evaluation of heterocyclic catechol mimics as inhibitors of catechol-O-methyltransferase (COMT): Structure with Cmpd32 ([1-(biphenyl-3-yl)-5-hydroxy-4-oxo-1,4-dihydropyridin-3-yl]boronic acid)
ComponentsCatechol O-methyltransferase
Keywordstransferase/transferase inhibitor / COMT / catechol-O-methyltransferase / transferase-transferase inhibitor complex
Function / homology
Function and homology information


Enzymatic degradation of dopamine by COMT / Enzymatic degradation of Dopamine by monoamine oxidase / norepinephrine secretion / response to dopamine / mastication / catecholamine catabolic process / catechol O-methyltransferase activity / catechol O-methyltransferase / developmental process / renal sodium excretion ...Enzymatic degradation of dopamine by COMT / Enzymatic degradation of Dopamine by monoamine oxidase / norepinephrine secretion / response to dopamine / mastication / catecholamine catabolic process / catechol O-methyltransferase activity / catechol O-methyltransferase / developmental process / renal sodium excretion / renal filtration / dopamine secretion / Methylation / renin secretion into blood stream / renal albumin absorption / artery development / habituation / cerebellar cortex morphogenesis / response to salt / dopamine catabolic process / cellular response to phosphate starvation / glomerulus development / norepinephrine metabolic process / synaptic transmission, dopaminergic / O-methyltransferase activity / response to angiotensin / cellular response to cocaine / cholesterol efflux / response to food / exploration behavior / response to corticosterone / prostaglandin metabolic process / glycogen metabolic process / startle response / dopamine metabolic process / detection of temperature stimulus involved in sensory perception of pain / behavioral fear response / response to amphetamine / response to cytokine / methyltransferase activity / visual learning / multicellular organism growth / memory / response to wounding / response to toxic substance / gene expression / methylation / response to oxidative stress / Potential therapeutics for SARS / response to hypoxia / response to xenobiotic stimulus / axon / intracellular membrane-bounded organelle / dendrite / synapse / magnesium ion binding / extracellular exosome / membrane / plasma membrane / cytosol
Similarity search - Function
Catechol O-methyltransferase, eukaryotic / Class I-like SAM-dependent O-methyltransferase / O-methyltransferase / SAM-dependent O-methyltransferase class I-type profile. / Vaccinia Virus protein VP39 / S-adenosyl-L-methionine-dependent methyltransferase superfamily / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-43H / S-ADENOSYLMETHIONINE / Catechol O-methyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsAllison, T. / Wolkenberg, S. / Sanders, J.M. / Soisson, S.M.
CitationJournal: Acs Med.Chem.Lett. / Year: 2015
Title: Synthesis and Evaluation of Heterocyclic Catechol Mimics as Inhibitors of Catechol-O-methyltransferase (COMT).
Authors: Harrison, S.T. / Poslusney, M.S. / Mulhearn, J.J. / Zhao, Z. / Kett, N.R. / Schubert, J.W. / Melamed, J.Y. / Allison, T.J. / Patel, S.B. / Sanders, J.M. / Sharma, S. / Smith, R.F. / Hall, D. ...Authors: Harrison, S.T. / Poslusney, M.S. / Mulhearn, J.J. / Zhao, Z. / Kett, N.R. / Schubert, J.W. / Melamed, J.Y. / Allison, T.J. / Patel, S.B. / Sanders, J.M. / Sharma, S. / Smith, R.F. / Hall, D.L. / Robinson, R.G. / Sachs, N.A. / Hutson, P.H. / Wolkenberg, S.E. / Barrow, J.C.
History
DepositionJan 25, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 15, 2015Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2017Group: Derived calculations / Refinement description ...Derived calculations / Refinement description / Source and taxonomy / Structure summary
Category: entity_src_gen / pdbx_struct_assembly ...entity_src_gen / pdbx_struct_assembly / pdbx_struct_oper_list / software / struct_keywords
Item: _entity_src_gen.pdbx_alt_source_flag / _pdbx_struct_assembly.oligomeric_details ..._entity_src_gen.pdbx_alt_source_flag / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_oper_list.symmetry_operation / _struct_keywords.text
Revision 1.2Sep 27, 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

Downloads & links

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Assembly

Deposited unit
A: Catechol O-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,1855
Polymers24,2601
Non-polymers9254
Water2,918162
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)43.812, 57.631, 98.249
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Catechol O-methyltransferase


Mass: 24259.889 Da / Num. of mol.: 1 / Fragment: unp residues 48-265 / Mutation: M51A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: COMT / Production host: Escherichia coli (E. coli) / References: UniProt: P21964, catechol O-methyltransferase

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Non-polymers , 5 types, 166 molecules

#2: Chemical ChemComp-43H / [1-(biphenyl-3-yl)-5-hydroxy-4-oxo-1,4-dihydropyridin-3-yl]boronic acid


Mass: 307.108 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H14BNO4
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-SAM / S-ADENOSYLMETHIONINE


Mass: 398.437 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H22N6O5S
#5: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID


Mass: 195.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 162 / 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: 2.56 Å3/Da / Density % sol: 51.89 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 7
Details: 0.1M HEPES, 30% PEG 6000; MA000474 (JCSG core IV), drop e12 :100uM ligand, 12mg/ml protein

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Jun 25, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.4→50 Å / Num. obs: 10266 / % possible obs: 100 % / Redundancy: 7.7 % / Rmerge(I) obs: 0.198 / Χ2: 1.565 / Net I/av σ(I): 14.149 / Net I/σ(I): 7.2 / Num. measured all: 79089
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.4-2.447.70.6965051.013100
2.44-2.497.80.6664951.034100
2.49-2.537.70.5844900.968100
2.53-2.597.80.5745151.06100
2.59-2.647.90.5474871.072100
2.64-2.77.80.4765051.211100
2.7-2.777.80.4065081.079100
2.77-2.857.90.4034891.251100
2.85-2.937.80.3565251.342100
2.93-3.027.90.2954951.486100
3.02-3.137.80.2635181.762100
3.13-3.267.80.2184961.69100
3.26-3.417.80.1885181.971100
3.41-3.587.80.1655172.207100
3.58-3.817.70.155092.082100
3.81-4.17.70.1345202.388100
4.1-4.527.70.1175162.173100
4.52-5.177.70.1055261.793100
5.17-6.517.50.1175431.651100
6.51-506.70.115891.98899.7

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
REFMAC5.2.0019refinement
PDB_EXTRACT3.15data extraction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4XUC

4xuc


Resolution: 2.4→49.69 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.911 / SU B: 7.444 / SU ML: 0.174 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.412 / ESU R Free: 0.264 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.241 484 4.8 %RANDOM
Rwork0.1679 9611 --
obs0.1713 9611 98.66 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 95.79 Å2 / Biso mean: 24.293 Å2 / Biso min: 9.51 Å2
Baniso -1Baniso -2Baniso -3
1-1.66 Å20 Å20 Å2
2---0.75 Å20 Å2
3----0.91 Å2
Refinement stepCycle: final / Resolution: 2.4→49.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1699 0 63 162 1924
Biso mean--36.44 31.65 -
Num. residues----218
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0221796
X-RAY DIFFRACTIONr_angle_refined_deg1.3162.0152438
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7345217
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.93124.93577
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.89315306
X-RAY DIFFRACTIONr_dihedral_angle_4_deg10.626159
X-RAY DIFFRACTIONr_chiral_restr0.0840.2274
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.021336
X-RAY DIFFRACTIONr_nbd_refined0.1880.2825
X-RAY DIFFRACTIONr_nbtor_refined0.3050.21194
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1640.2157
X-RAY DIFFRACTIONr_metal_ion_refined0.0170.21
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2020.231
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1840.29
X-RAY DIFFRACTIONr_mcbond_it0.6181.51130
X-RAY DIFFRACTIONr_mcangle_it1.02521759
X-RAY DIFFRACTIONr_scbond_it1.6813767
X-RAY DIFFRACTIONr_scangle_it2.7434.5679
LS refinement shellResolution: 2.399→2.461 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.316 27 -
Rwork0.195 702 -
all-729 -
obs--99.45 %

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