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- PDB-2rbe: The discovery of 2-anilinothiazolones as 11beta-HSD1 inhibitors -

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Basic information

Entry
Database: PDB / ID: 2rbe
TitleThe discovery of 2-anilinothiazolones as 11beta-HSD1 inhibitors
ComponentsCorticosteroid 11-beta-dehydrogenase isozyme 1
KeywordsOXIDOREDUCTASE / Alpha Beta / 3-Layer(aba) Sandwich / Rossmann fold / NAD(P)-binding Rossmann-like Domain / Endoplasmic reticulum / Glycoprotein / Lipid metabolism / Membrane / Microsome / NADP / Signal-anchor / Steroid metabolism / Transmembrane / Polymorphism
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-NDP / Chem-ZMG / 11-beta-hydroxysteroid dehydrogenase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.9 Å
AuthorsZhang, J. / Jordan, S.R. / Li, V.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2007
Title: The discovery of 2-anilinothiazolones as 11beta-HSD1 inhibitors.
Authors: Yuan, C. / St Jean, D.J. / Liu, Q. / Cai, L. / Li, A. / Han, N. / Moniz, G. / Askew, B. / Hungate, R.W. / Johansson, L. / Tedenborg, L. / Pyring, D. / Williams, M. / Hale, C. / Chen, M. / ...Authors: Yuan, C. / St Jean, D.J. / Liu, Q. / Cai, L. / Li, A. / Han, N. / Moniz, G. / Askew, B. / Hungate, R.W. / Johansson, L. / Tedenborg, L. / Pyring, D. / Williams, M. / Hale, C. / Chen, M. / Cupples, R. / Zhang, J. / Jordan, S. / Bartberger, M.D. / Sun, Y. / Emery, M. / Wang, M. / Fotsch, C.
History
DepositionSep 18, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 15, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 25, 2017Group: Refinement description / Category: software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.date / _software.language / _software.location / _software.name / _software.type / _software.version
Revision 1.3Oct 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 1.4Feb 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)125,93712
Polymers121,9464
Non-polymers3,9918
Water8,413467
1
A: Corticosteroid 11-beta-dehydrogenase isozyme 1
B: Corticosteroid 11-beta-dehydrogenase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,9686
Polymers60,9732
Non-polymers1,9954
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8410 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)62,9686
Polymers60,9732
Non-polymers1,9954
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8610 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.906, 138.660, 155.827
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 / Fragment: dehydrogenase domain / Mutation: C272S
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-ZMG / (5R)-2-[(2-fluorophenyl)amino]-5-(1-methylethyl)-1,3-thiazol-4(5H)-one / (R)-2-(2-fluorophenylamino)-5-isopropylthiazol-4(5H)-one


Mass: 252.308 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C12H13FN2OS
#3: 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
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 467 / 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: 2.17 Å3/Da / Density % sol: 43.22 %

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorDate: Jul 15, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. obs: 80467 / % possible obs: 95.5 % / Rmerge(I) obs: 0.083 / Χ2: 0.944 / Net I/σ(I): 7.7
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique allΧ2% possible all
1.9-1.930.53539940.56396
1.93-1.970.4540310.50997.2
1.97-2.010.41340370.51598.1
2.01-2.050.34840970.53797.8
2.05-2.090.32140060.67197.3
2.09-2.140.26340920.697.5
2.14-2.190.22740460.63297.3
2.19-2.250.21240250.68896.7
2.25-2.320.18240700.68596.9
2.32-2.390.15540100.6896.6
2.39-2.480.13640230.76696.5
2.48-2.580.11840600.82396.1
2.58-2.70.10939870.87895.9
2.7-2.840.08940350.90495.6
2.84-3.020.08240161.01895.1
3.02-3.250.07440041.24994.6
3.25-3.580.0739691.61893.8
3.58-4.090.06139891.77292.8
4.09-5.160.05439191.6891.3
5.16-500.05340571.67388.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
CNSrefinement
PDB_EXTRACT3data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→50 Å / σ(F): 0
RfactorNum. reflection% reflection
Rfree0.264 6280 7.4 %
Rwork0.219 --
obs-77180 91.3 %
Displacement parametersBiso mean: 29.333 Å2
Baniso -1Baniso -2Baniso -3
1--4.008 Å20 Å20 Å2
2---0.781 Å20 Å2
3---4.789 Å2
Refinement stepCycle: LAST / Resolution: 1.9→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7895 0 256 467 8618
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_angle_d1.458
X-RAY DIFFRACTIONc_mcbond_it1.3351.5
X-RAY DIFFRACTIONc_scbond_it2.1692
X-RAY DIFFRACTIONc_mcangle_it1.9542
X-RAY DIFFRACTIONc_scangle_it3.1272.5
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2lig1AB.xprmdna-rna.top
X-RAY DIFFRACTION3water_rep.paramwater.top
X-RAY DIFFRACTION4N1234.xprmion.top
X-RAY DIFFRACTION5lig2AB.xprm

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