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- PDB-1wv0: Crystallographic studies on acyl ureas, a new class of inhibitors... -

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Basic information

Entry
Database: PDB / ID: 1wv0
TitleCrystallographic studies on acyl ureas, a new class of inhibitors of glycogen phosphorylase. Broad specificity of the allosteric site
ComponentsGlycogen phosphorylase, muscle form
KeywordsTRANSFERASE / glycogenolysis / type 2 diabetes
Function / homology
Function and homology information


glycogen phosphorylase / glycogen phosphorylase activity / : / : / glycogen catabolic process / skeletal muscle myofibril / pyridoxal phosphate binding / nucleotide binding
Similarity search - Function
Glycosyl transferase, family 35 / Glycogen/starch/alpha-glucan phosphorylase / Phosphorylase pyridoxal-phosphate attachment site / Carbohydrate phosphorylase / Phosphorylase pyridoxal-phosphate attachment site. / Glycogen Phosphorylase B; / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-BN4 / PYRIDOXAL-5'-PHOSPHATE / Glycogen phosphorylase, muscle form
Similarity search - Component
Biological speciesOryctolagus cuniculus (rabbit)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.26 Å
AuthorsOikonomakos, N.G. / Kosmopoulou, M.N. / Chrysina, E.D. / Leonidas, D.D. / Klabunde, T. / Wendt, K.U. / Defossa, E.
Citation
Journal: Protein Sci. / Year: 2005
Title: Crystallographic studies on acyl ureas, a new class of glycogen phosphorylase inhibitors, as potential antidiabetic drugs
Authors: Oikonomakos, N.G. / Kosmopoulou, M.N. / Chrysina, E.D. / Leonidas, D.D. / Kostas, I.D. / Wendt, K.U. / Klabunde, T. / Defossa, E.
#1: Journal: J.Med.Chem. / Year: 2005
Title: Acyl ureas as human liver glycogen phosphorylase inhibitors for the treatment of type 2 diabetes
Authors: Klabunde, T. / Wendt, U.K. / Kadereit, D. / Brachvogel, V. / Burger, H.-J. / Herling, A.W. / Oikonomakos, N.G. / Kosmopoulou, M.N. / Schmoll, D. / Sarubbi, E. / von Roedern, E. / Schonafinger, K. / Defossa, E.
#2: Journal: Structure / Year: 1997
Title: The structure of glycogen phosphorylase b with an alkyldihydropyridine-dicarboxylic acid compound, a novel and potent inhibitor
Authors: Zographos, S.E. / Oikonomakos, N.G. / Tsitsanou, K.E. / Leonidas, D.D. / Chrysina, E.D. / Skamnaki, V.T. / Bischoff, H. / Goldmann, S. / Watson, K.A. / Johnson, L.N.
#3: Journal: Protein Sci. / Year: 1999
Title: Allosteric inhibition of glycogen phosphorylase a by the potential antidiabetic drug 3-isopropyl 4-(2-chlorophenyl)-1,4-dihydro-1-ethyl-2-methyl-pyridine-3,5,6-tricarbo xylate
Authors: Oikonomakos, N.G. / Tsitsanou, K.E. / Zographos, S.E. / Skamnaki, V.T. / Goldmann, S. / Bischoff, H.
#4: Journal: J.Med.Chem. / Year: 2004
Title: Identification, synthesis, and characterization of new glycogen phosphorylase inhibitors binding to the allosteric AMP site
Authors: Kristiansen, M. / Andersen, B. / Iversen, L.F. / Westergaard, N.
History
DepositionDec 10, 2004Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 10, 2005Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Derived calculations / Version format compliance

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Glycogen phosphorylase, muscle form
hetero molecules


Theoretical massNumber of molelcules
Total (without water)97,9783
Polymers97,2911
Non-polymers6862
Water4,252236
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A: Glycogen phosphorylase, muscle form
hetero molecules

A: Glycogen phosphorylase, muscle form
hetero molecules


Theoretical massNumber of molelcules
Total (without water)195,9556
Polymers194,5822
Non-polymers1,3734
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_556y,x,-z+11
Buried area7430 Å2
ΔGint-54 kcal/mol
Surface area57360 Å2
MethodPISA, PQS
Unit cell
Length a, b, c (Å)128.650, 128.650, 116.065
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212
DetailsDimeric glycogen phosphorylase is the physiologiacally active species

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Components

#1: Protein Glycogen phosphorylase, muscle form / Myophosphorylase


Mass: 97291.203 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Oryctolagus cuniculus (rabbit) / Tissue: Muscle / References: UniProt: P00489, glycogen phosphorylase
#2: Chemical ChemComp-PLP / PYRIDOXAL-5'-PHOSPHATE / VITAMIN B6 Phosphate


Mass: 247.142 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H10NO6P
#3: Chemical ChemComp-BN4 / 4-[4-({[(2,4-DICHLOROBENZOYL)AMINO]CARBONYL}AMINO)-2,3-DIMETHYLPHENOXY]BUTANOIC ACID / 4-{4-[3-(2,4-DICHLORO-BENZOYL)-UREIDO]-2,3-DIMETHYL-PHENOXY}-BUTYRIC ACID


Mass: 439.289 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H20Cl2N2O5
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 236 / 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: 2.43 Å3/Da / Density % sol: 48.91 %
Crystal growTemperature: 298 K / Method: small tubes / pH: 6.7
Details: 10mM BES, 3mM DTT, pH 6.7, SMALL TUBES, temperature 298K

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Data collection

DiffractionMean temperature: 298 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Apr 19, 2001
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.26→29.49 Å / Num. all: 246348 / Num. obs: 44282 / % possible obs: 95.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 4.3 % / Biso Wilson estimate: 33.9 Å2 / Rmerge(I) obs: 0.116 / Net I/σ(I): 9.9
Reflection shellResolution: 2.26→2.3 Å / Redundancy: 3.2 % / Rmerge(I) obs: 0.551 / Mean I/σ(I) obs: 2 / Num. unique all: 1875 / % possible all: 81.9

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Processing

Software
NameVersionClassification
X-PLOR3.851refinement
HKL-2000data reduction
SCALEPACKdata scaling
X-PLORphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.26→29.49 Å / Rfactor Rfree error: 0.005 / Data cutoff high absF: 10000000 / Data cutoff low absF: 0.001 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber / Details: BULK SOLVENT MODEL USED
RfactorNum. reflection% reflectionSelection details
Rfree0.24 2241 5.1 %RANDOM
Rwork0.197 ---
obs0.197 44225 95.8 %-
Displacement parametersBiso mean: 34.6 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.34 Å0.27 Å
Luzzati d res low-5 Å
Luzzati sigma a0.43 Å0.38 Å
Refinement stepCycle: LAST / Resolution: 2.26→29.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6634 0 44 236 6914
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONx_bond_d0.007
X-RAY DIFFRACTIONx_angle_deg1.3
X-RAY DIFFRACTIONx_dihedral_angle_d25.3
X-RAY DIFFRACTIONx_improper_angle_d0.7
X-RAY DIFFRACTIONx_mcbond_it1.731.5
X-RAY DIFFRACTIONx_mcangle_it2.842
X-RAY DIFFRACTIONx_scbond_it2.932
X-RAY DIFFRACTIONx_scangle_it4.592.5
LS refinement shellResolution: 2.26→2.4 Å / Rfactor Rfree error: 0.02 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.364 341 5.1 %
Rwork0.345 6338 -
obs--88.2 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMTOPHCSDX.PRO
X-RAY DIFFRACTION2b83.paramb83.top
X-RAY DIFFRACTION3plp.paramplp.top
X-RAY DIFFRACTION4water.top
X-RAY DIFFRACTION5lysh.top

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