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- PDB-3ey4: Further studies with the 2-amino-1,3-thiazol-4(5H)-one class of 1... -

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Basic information

Entry
Database: PDB / ID: 3ey4
TitleFurther studies with the 2-amino-1,3-thiazol-4(5H)-one class of 11-hydroxysteroid dehydrogenase type 1 (11-HSD1) inhibitors: Reducing pregnane X receptor (PXR) activity and exploring activity in a monkey pharmacodynamic model
Components11-beta-Hydroxysteroid Dehydrogenase 1
KeywordsOXIDOREDUCTASE / Endoplasmic reticulum / Glycoprotein / Lipid metabolism / Membrane / NADP / Polymorphism / Signal-anchor / Steroid metabolism / Transmembrane / Alpha Beta / 3-Layer(aba) Sandwich / Rossmann fold / NAD(P)-binding Rossmann-like Domain / inhibitor / drug design
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-352 / Chem-NDP / 11-beta-hydroxysteroid dehydrogenase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3 Å
AuthorsZhang, J.D. / Jordan, S.R. / Li, V.
CitationJournal: To be Published / Year: 2008
Title: Further studies with the 2-amino-1,3-thiazol-4(5H)-one class of 11-hydroxysteroid dehydrogenase type 1 (11-HSD1) inhibitors: Reducing pregnane X receptor (PXR) activity and exploring activity ...Title: Further studies with the 2-amino-1,3-thiazol-4(5H)-one class of 11-hydroxysteroid dehydrogenase type 1 (11-HSD1) inhibitors: Reducing pregnane X receptor (PXR) activity and exploring activity in a monkey pharmacodynamic model
Authors: Christopher, F. / Bartberger, M.D. / Bercot, E.A. / Chen, M. / Cupples, R. / Emery, M. / Fretland, J. / Guram, A. / Hale, C. / Han, N.H. / Hickman, D. / Hungate, R.W. / Hayashi, M. / ...Authors: Christopher, F. / Bartberger, M.D. / Bercot, E.A. / Chen, M. / Cupples, R. / Emery, M. / Fretland, J. / Guram, A. / Hale, C. / Han, N.H. / Hickman, D. / Hungate, R.W. / Hayashi, M. / Komorowski, R. / Liu, Q.Y. / Matsumoto, G. / Jean, D.J.St. / Ursu, S. / Voniant, M. / Xu, G.F. / Ye, Q.P. / Yuan, C. / Zhang, J.D. / Zhang, X.P. / Tu, H. / Wang, M.H.
History
DepositionOct 17, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 11, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 25, 2017Group: Refinement description / Category: software
Revision 1.3Jul 24, 2019Group: Data collection / Refinement description / Category: software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.location / _software.name / _software.type
Revision 1.4Oct 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 1.5Dec 27, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: 11-beta-Hydroxysteroid Dehydrogenase 1
B: 11-beta-Hydroxysteroid Dehydrogenase 1
C: 11-beta-Hydroxysteroid Dehydrogenase 1
D: 11-beta-Hydroxysteroid Dehydrogenase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)126,16912
Polymers121,9464
Non-polymers4,2238
Water0
1
A: 11-beta-Hydroxysteroid Dehydrogenase 1
B: 11-beta-Hydroxysteroid Dehydrogenase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,0846
Polymers60,9732
Non-polymers2,1124
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7000 Å2
ΔGint-55 kcal/mol
Surface area20700 Å2
MethodPISA
2
C: 11-beta-Hydroxysteroid Dehydrogenase 1
D: 11-beta-Hydroxysteroid Dehydrogenase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,0846
Polymers60,9732
Non-polymers2,1124
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7160 Å2
ΔGint-58 kcal/mol
Surface area20640 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.043, 138.482, 155.336
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein
11-beta-Hydroxysteroid Dehydrogenase 1 / E.C.1.1.1.146 / Corticosteroid 11-beta-dehydrogenase isozyme 1 / 11-beta-HSD1 / 11-DH


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-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-352 / (5S)-2-{[(1S)-1-(4-fluorophenyl)ethyl]amino}-5-(1-hydroxy-1-methylethyl)-5-methyl-1,3-thiazol-4(5H)-one


Mass: 310.387 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C15H19FN2O2S

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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: 43.13 % / Mosaicity: 0.561 °
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: PEG 3350 25%, Na Citrate 0.1M, ammonium acetate 0.2M, 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: Sep 21, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.9→50 Å / Num. obs: 24635 / % possible obs: 97.6 % / Redundancy: 4.3 % / Rmerge(I) obs: 0.113 / Χ2: 1.128 / Net I/σ(I): 12.014
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.9-32.60.61420410.96283.2
3-3.123.40.53123271.05993.6
3.12-3.274.40.40124621.14599.5
3.27-3.444.80.30124741.2299.7
3.44-3.654.80.23124821.40799.8
3.65-3.944.70.15325021.15499.9
3.94-4.334.70.125171.10699.9
4.33-4.964.70.07325501.034100
4.96-6.244.60.07825691.01199.9
6.24-504.30.04127111.04199.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
CNXrefinement
SCALEPACKdata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACT3.006data extraction
HKL-2000data collection
DENZOdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3→50 Å / Occupancy max: 1 / Occupancy min: 1 / Data cutoff high absF: 1000 / Data cutoff low absF: 0 / σ(F): 0
RfactorNum. reflection% reflection
Rfree0.319 1643 7.5 %
Rwork0.219 --
all-20693 -
obs-20693 94 %
Displacement parametersBiso max: 99.77 Å2 / Biso mean: 43.133 Å2 / Biso min: 5.9 Å2
Baniso -1Baniso -2Baniso -3
1--6.462 Å20 Å20 Å2
2--0.939 Å20 Å2
3---5.523 Å2
Refinement stepCycle: LAST / Resolution: 3→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7895 0 276 0 8171
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.01
X-RAY DIFFRACTIONc_angle_deg1.853
X-RAY DIFFRACTIONc_mcbond_it1.2841.5
X-RAY DIFFRACTIONc_scbond_it1.7092
X-RAY DIFFRACTIONc_mcangle_it2.2392
X-RAY DIFFRACTIONc_scangle_it2.6982.5
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1MSI_CNX_TOPPAR:protein_rep.paramMSI_CNX_TOPPAR:protein.top
X-RAY DIFFRACTION2MSI_CNX_TOPPAR:dna-rna_rep.paramMSI_CNX_TOPPAR:dna-rna.top
X-RAY DIFFRACTION3MSI_CNX_TOPPAR:water_rep.paramMSI_CNX_TOPPAR:water.top
X-RAY DIFFRACTION4N1234.xprmMSI_CNX_TOPPAR:ion.top
X-RAY DIFFRACTION5lig12AB.xprm

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