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- PDB-3byz: 2-Amino-1,3-thiazol-4(5H)-ones as Potent and Selective 11-Hydroxy... -

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Basic information

Entry
Database: PDB / ID: 3byz
Title2-Amino-1,3-thiazol-4(5H)-ones as Potent and Selective 11-Hydroxysteroid Dehydrogenase Type 1 Inhibitors
ComponentsCorticosteroid 11-beta-dehydrogenase isozyme 1
KeywordsOXIDOREDUCTASE / alpha beta / 3-layer (aba) sandwich / rossmann fold / NAD(P)-binding rossmann-like domain. amino thiazole inhibitor / Endoplasmic reticulum / Glycoprotein / Lipid metabolism / Membrane / Microsome / NADP / Polymorphism / Signal-anchor / Steroid metabolism / Transmembrane / ----
Function / homology
Function and homology information


11beta-hydroxysteroid dehydrogenase / 11-beta-hydroxysteroid dehydrogenase (NADP+) activity / cortisol dehydrogenase activity / 7beta-hydroxysteroid dehydrogenase (NADP+) / 7-beta-hydroxysteroid dehydrogenase (NADP+) activity / Glucocorticoid biosynthesis / steroid catabolic process / Prednisone ADME / steroid binding / lung development ...11beta-hydroxysteroid dehydrogenase / 11-beta-hydroxysteroid dehydrogenase (NADP+) activity / cortisol dehydrogenase activity / 7beta-hydroxysteroid dehydrogenase (NADP+) / 7-beta-hydroxysteroid dehydrogenase (NADP+) activity / Glucocorticoid biosynthesis / steroid catabolic process / Prednisone ADME / steroid binding / lung development / NADP binding / intracellular membrane-bounded organelle / endoplasmic reticulum membrane / protein homodimerization activity / membrane
Similarity search - Function
short chain dehydrogenase / Short-chain dehydrogenase/reductase, conserved site / Short-chain dehydrogenases/reductases family signature. / Short-chain dehydrogenase/reductase SDR / NAD(P)-binding Rossmann-like Domain / NAD(P)-binding domain superfamily / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-H11 / Chem-NDP / 11-beta-hydroxysteroid dehydrogenase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.69 Å
AuthorsZhang, J. / Jordan, S.R. / Li, V.
CitationJournal: J.Med.Chem. / Year: 2008
Title: 2-amino-1,3-thiazol-4(5H)-ones as potent and selective 11beta-hydroxysteroid dehydrogenase type 1 inhibitors: enzyme-ligand co-crystal structure and demonstration of pharmacodynamic effects in C57Bl/6 mice.
Authors: Johansson, L. / Fotsch, C. / Bartberger, M.D. / Castro, V.M. / Chen, M. / Emery, M. / Gustafsson, S. / Hale, C. / Hickman, D. / Homan, E. / Jordan, S.R. / Komorowski, R. / Li, A. / McRae, K. ...Authors: Johansson, L. / Fotsch, C. / Bartberger, M.D. / Castro, V.M. / Chen, M. / Emery, M. / Gustafsson, S. / Hale, C. / Hickman, D. / Homan, E. / Jordan, S.R. / Komorowski, R. / Li, A. / McRae, K. / Moniz, G. / Matsumoto, G. / Orihuela, C. / Palm, G. / Veniant, M. / Wang, M. / Williams, M. / Zhang, J.
History
DepositionJan 16, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 12, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 20, 2021Group: Database references / Derived calculations / Category: database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Feb 21, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Corticosteroid 11-beta-dehydrogenase isozyme 1
B: Corticosteroid 11-beta-dehydrogenase isozyme 1
C: Corticosteroid 11-beta-dehydrogenase isozyme 1
D: Corticosteroid 11-beta-dehydrogenase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)126,05712
Polymers121,9464
Non-polymers4,1118
Water0
1
A: Corticosteroid 11-beta-dehydrogenase isozyme 1
B: Corticosteroid 11-beta-dehydrogenase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,0296
Polymers60,9732
Non-polymers2,0564
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6990 Å2
MethodPISA
2
C: Corticosteroid 11-beta-dehydrogenase isozyme 1
D: Corticosteroid 11-beta-dehydrogenase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,0296
Polymers60,9732
Non-polymers2,0564
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7270 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.036, 138.480, 155.022
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein
Corticosteroid 11-beta-dehydrogenase isozyme 1 / 11-DH / 11-beta-hydroxysteroid dehydrogenase 1 / 11-beta-HSD1


Mass: 30486.426 Da / Num. of mol.: 4 / Mutation: C266S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSD11B1, HSD11, HSD11L / Production host: Escherichia coli (E. coli)
References: UniProt: P28845, 11beta-hydroxysteroid dehydrogenase
#2: Chemical
ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Nicotinamide adenine dinucleotide phosphate


Mass: 745.421 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#3: Chemical
ChemComp-H11 / (5S)-2-(cyclooctylamino)-5-methyl-5-propyl-1,3-thiazol-4(5H)-one


Mass: 282.445 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C15H26N2OS

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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: 2.16 Å3/Da / Density % sol: 43 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: 25% PEG3350, 0.1M NaCitrate, 0.2M AmAc, pH 5.6, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Dec 1, 2004 / Details: mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.69→50 Å / Num. all: 30162 / Num. obs: 30027 / % possible obs: 99.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Biso Wilson estimate: 6.4 Å2 / Rmerge(I) obs: 0.135 / Net I/σ(I): 5.6
Reflection shellResolution: 2.7→2.8 Å / Redundancy: 6 % / Rmerge(I) obs: 0.869 / Mean I/σ(I) obs: 2 / Num. unique all: 2938 / % possible all: 99.6

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
ADSCQuantumdata collection
HKL-2000data reduction
SCALEPACKdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.69→50 Å / Cor.coef. Fo:Fc: 0.925 / Cor.coef. Fo:Fc free: 0.861 / SU B: 15.624 / SU ML: 0.328 / Cross valid method: THROUGHOUT / ESU R Free: 0.431 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.29333 1523 5.1 %RANDOM
Rwork0.21848 ---
obs0.2223 28447 99.54 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 38.267 Å2
Baniso -1Baniso -2Baniso -3
1-0.33 Å20 Å20 Å2
2--0.62 Å20 Å2
3----0.95 Å2
Refinement stepCycle: LAST / Resolution: 2.69→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7887 0 268 0 8155
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.0228308
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.312.00511257
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.17851025
X-RAY DIFFRACTIONr_dihedral_angle_2_deg41.6523.813299
X-RAY DIFFRACTIONr_dihedral_angle_3_deg21.116151458
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.8081536
X-RAY DIFFRACTIONr_chiral_restr0.1290.21335
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.025904
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2650.24440
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3290.25753
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.170.2338
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2340.253
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0780.23
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.0051.55279
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.74628222
X-RAY DIFFRACTIONr_scbond_it2.53833451
X-RAY DIFFRACTIONr_scangle_it4.0074.53035
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.694→2.764 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.325 98 -
Rwork0.305 2062 -
obs--98.63 %

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