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- PDB-3d3e: Crystal Structure of Human 11-beta-Hydroxysteroid Dehydrogenase (... -

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Basic information

Entry
Database: PDB / ID: 3d3e
TitleCrystal Structure of Human 11-beta-Hydroxysteroid Dehydrogenase (HSD1) in Complex with Benzamide Inhibitor
ComponentsCorticosteroid 11-beta-dehydrogenase isozyme 1
KeywordsOXIDOREDUCTASE / 11beta / hydroxysteroid / dehydrogenase / Endoplasmic reticulum / Glycoprotein / Lipid metabolism / Membrane / Microsome / NADP / Polymorphism / Signal-anchor / Steroid metabolism / Transmembrane
Function / homology
Function and homology information


11-beta-hydroxysteroid dehydrogenase (NADP+) activity / 11beta-hydroxysteroid dehydrogenase / cortisol dehydrogenase activity / 7beta-hydroxysteroid dehydrogenase (NADP+) / 7-beta-hydroxysteroid dehydrogenase (NADP+) activity / Glucocorticoid biosynthesis / steroid catabolic process / Prednisone ADME / steroid binding / lung development ...11-beta-hydroxysteroid dehydrogenase (NADP+) activity / 11beta-hydroxysteroid dehydrogenase / 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-D3E / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 11-beta-hydroxysteroid dehydrogenase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsWang, Z. / Sudom, A. / Liu, J. / Walker, N.P.
CitationJournal: J.Med.Chem. / Year: 2008
Title: Discovery of Novel, Potent Benzamide Inhibitors of 11beta-Hydroxysteroid Dehydrogenase Type 1 (11beta-HSD1) Exhibiting Oral Activity in an Enzyme Inhibition ex Vivo Model
Authors: Julian, L.D. / Wang, Z. / Bostick, T. / Caille, S. / Choi, R. / Degraffenreid, M. / Di, Y. / He, X. / Hungate, R.W. / Jaen, J.C. / Liu, J. / Monshouwer, M. / McMinn, D. / Rew, Y. / Sudom, A. ...Authors: Julian, L.D. / Wang, Z. / Bostick, T. / Caille, S. / Choi, R. / Degraffenreid, M. / Di, Y. / He, X. / Hungate, R.W. / Jaen, J.C. / Liu, J. / Monshouwer, M. / McMinn, D. / Rew, Y. / Sudom, A. / Sun, D. / Tu, H. / Ursu, S. / Walker, N. / Yan, X. / Ye, Q. / Powers, J.P.
History
DepositionMay 9, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 1, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 20, 2021Group: Database references / Derived calculations / Source and taxonomy
Category: database_2 / entity_src_gen ...database_2 / entity_src_gen / 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 / _entity_src_gen.pdbx_gene_src_ncbi_taxonomy_id / _entity_src_gen.pdbx_host_org_ncbi_taxonomy_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Aug 30, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)132,05112
Polymers127,3484
Non-polymers4,7048
Water81145
1
A: Corticosteroid 11-beta-dehydrogenase isozyme 1
B: Corticosteroid 11-beta-dehydrogenase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,0266
Polymers63,6742
Non-polymers2,3524
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6950 Å2
ΔGint-51.7 kcal/mol
Surface area21190 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)66,0266
Polymers63,6742
Non-polymers2,3524
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6770 Å2
ΔGint-51.3 kcal/mol
Surface area21110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.700, 152.846, 73.708
Angle α, β, γ (deg.)90.00, 92.11, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 31836.875 Da / Num. of mol.: 4 / Mutation: S272C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSD11B1, HSD11, HSD11L / Plasmid: pET15 / Production host: Escherichia coli (E. coli) / Strain (production host): DH10a
References: UniProt: P28845, 11beta-hydroxysteroid dehydrogenase
#2: Chemical
ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE


Mass: 743.405 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#3: Chemical
ChemComp-D3E / N-cyclopropyl-N-(trans-4-pyridin-3-ylcyclohexyl)-4-[(1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl]benzamide


Mass: 432.479 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C24H27F3N2O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 45 / 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: 2.51 Å3/Da / Density % sol: 50.92 %
Crystal growTemperature: 289 K / pH: 6.4
Details: 19% PEG 3350, 0.1 M MES 6.4, VAPOR DIFFUSION, SITTING DROP, temperature 289K

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Data collection

DiffractionMean temperature: 77.2 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.997
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 11, 2005
RadiationMonochromator: DOUBLE-CRYSTAL SI (III) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.997 Å / Relative weight: 1
ReflectionResolution: 2.6→76.249 Å / Num. obs: 38140 / % possible obs: 99.2 % / Observed criterion σ(I): 0 / Redundancy: 3.7 % / Biso Wilson estimate: 71.4 Å2 / Rmerge(I) obs: 0.045 / Net I/σ(I): 18.4
Reflection shellResolution: 2.6→2.74 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.38 / Mean I/σ(I) obs: 3.4 / % possible all: 99.1

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Processing

Software
NameVersionClassification
REFMAC5.4.0069refinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1XU9

1xu9


Resolution: 2.6→66.37 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.892 / SU B: 13.276 / SU ML: 0.287 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 1.017 / ESU R Free: 0.359 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.283 1922 5 %RANDOM
Rwork0.227 ---
obs0.23 36233 99.1 %-
all-38140 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 59.14 Å2
Baniso -1Baniso -2Baniso -3
1--0.32 Å20 Å2-3.49 Å2
2---0.23 Å20 Å2
3---0.29 Å2
Refinement stepCycle: LAST / Resolution: 2.6→66.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7957 0 316 45 8318
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0228430
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.2132.01411440
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.09251031
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.6924.066305
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.081151467
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.6071536
X-RAY DIFFRACTIONr_chiral_restr0.070.21352
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.025984
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.4091.55143
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.75428265
X-RAY DIFFRACTIONr_scbond_it0.73933287
X-RAY DIFFRACTIONr_scangle_it1.34.53163
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.6→2.67 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.346 146 -
Rwork0.305 2637 -
obs--99.18 %

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