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- PDB-3d4n: Crystal Structure of Human 11-beta-Hydroxysteroid Dehydrogenase (... -

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Basic information

Entry
Database: PDB / ID: 3d4n
TitleCrystal Structure of Human 11-beta-Hydroxysteroid Dehydrogenase (HSD1) in Complex with Sulfonamide 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


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-D4N / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 11-beta-hydroxysteroid dehydrogenase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.5 Å
AuthorsWang, Z. / Liu, J. / Sudom, A. / 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 14, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 22, 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 1.3Feb 21, 2024Group: 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: 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)132,11912
Polymers127,3484
Non-polymers4,7728
Water3,009167
1
A: Corticosteroid 11-beta-dehydrogenase isozyme 1
B: Corticosteroid 11-beta-dehydrogenase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,0606
Polymers63,6742
Non-polymers2,3864
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6680 Å2
ΔGint-48.8 kcal/mol
Surface area21090 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)66,0606
Polymers63,6742
Non-polymers2,3864
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6670 Å2
ΔGint-47.7 kcal/mol
Surface area20930 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.619, 153.759, 73.908
Angle α, β, γ (deg.)90.00, 93.11, 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 / Fragment: Lumenal domain / Mutation: C272S
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 / Nicotinamide adenine dinucleotide phosphate


Mass: 743.405 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#3: Chemical
ChemComp-D4N / 1-{[(3R)-3-methyl-4-({4-[(1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl]phenyl}sulfonyl)piperazin-1-yl]methyl}cyclopropanecarboxamide


Mass: 449.488 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C19H26F3N3O4S
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 167 / 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: 2.52 Å3/Da / Density % sol: 51.24 %
Crystal growTemperature: 289 K / Method: vapor diffusion / pH: 6.4
Details: 19% PEG 3350, 0.1 M MES 6.4, vapor diffusion, temperature 289K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1.5418 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Mar 10, 2005 / Details: 3X3 CCD ARRAY
RadiationMonochromator: DOUBLE-CRYSTAL, SI (111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.5→76.923 Å / Num. all: 41684 / Num. obs: 40775 / % possible obs: 93.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 2.5 % / Biso Wilson estimate: 44.405 Å2 / Rmerge(I) obs: 0.123 / Net I/σ(I): 3.8
Reflection shellResolution: 2.5→2.64 Å / Redundancy: 2.5 % / Rmerge(I) obs: 0.164 / Mean I/σ(I) obs: 4.2 / Num. unique all: 5681 / % possible all: 89.7

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Processing

Software
NameVersionClassificationNB
SCALA3.2.5data scaling
REFMAC5.4.0069refinement
PDB_EXTRACT3.005data extraction
ADSCQuantumdata collection
MOSFLMdata reduction
MOLREPphasing
RefinementResolution: 2.5→76.92 Å / Cor.coef. Fo:Fc: 0.907 / Cor.coef. Fo:Fc free: 0.879 / SU B: 8.87 / SU ML: 0.203 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R: 0.836 / ESU R Free: 0.318 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.259 2011 4.9 %RANDOM
Rwork0.227 ---
obs0.228 40747 93.46 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 26.934 Å2
Baniso -1Baniso -2Baniso -3
1-2.93 Å20 Å2-1.09 Å2
2---0.6 Å20 Å2
3----2.45 Å2
Refinement stepCycle: LAST / Resolution: 2.5→76.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8106 0 312 167 8585
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0228586
X-RAY DIFFRACTIONr_angle_refined_deg1.1072.01111666
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.5451040
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.06224.101317
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.324151529
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.9951537
X-RAY DIFFRACTIONr_chiral_restr0.0710.21388
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.026049
X-RAY DIFFRACTIONr_mcbond_it0.2981.55203
X-RAY DIFFRACTIONr_mcangle_it0.55428402
X-RAY DIFFRACTIONr_scbond_it0.5733383
X-RAY DIFFRACTIONr_scangle_it0.9944.53252
LS refinement shellResolution: 2.5→2.565 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.313 142 -
Rwork0.284 2739 -
all-2881 -
obs--88.84 %

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