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- PDB-3ch6: Crystal Structure of 11beta-HSD1 Double Mutant (L262R, F278E) Com... -

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Basic information

Entry
Database: PDB / ID: 3ch6
TitleCrystal Structure of 11beta-HSD1 Double Mutant (L262R, F278E) Complexed with (3,3-dimethylpiperidin-1-yl)(6-(3-fluoro-4-methylphenyl)pyridin-2-yl)methanone
ComponentsCorticosteroid 11-beta-dehydrogenase isozyme 1
KeywordsOXIDOREDUCTASE / 11B-HSD1 / sdr / dehydrogenase / hydroxysteroid / inhibitor
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-311 / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 11-beta-hydroxysteroid dehydrogenase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / molecular replacement / Resolution: 2.35 Å
AuthorsSheriff, S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2008
Title: Pyridine amides as potent and selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1
Authors: Wang, H. / Ruan, Z. / Li, J.J. / Simpkins, L.M. / Smirk, R.A. / Wu, S.C. / Hutchins, R.D. / Nirschl, D.S. / Van Kirk, K. / Cooper, C.B. / Sutton, J.C. / Ma, Z. / Golla, R. / Seethala, R. / ...Authors: Wang, H. / Ruan, Z. / Li, J.J. / Simpkins, L.M. / Smirk, R.A. / Wu, S.C. / Hutchins, R.D. / Nirschl, D.S. / Van Kirk, K. / Cooper, C.B. / Sutton, J.C. / Ma, Z. / Golla, R. / Seethala, R. / Salyan, M.E. / Nayeem, A. / Krystek, S.R. / Sheriff, S. / Camac, D.M. / Morin, P.E. / Carpenter, B. / Robl, J.A. / Zahler, R. / Gordon, D.A. / Hamann, L.G.
History
DepositionMar 7, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 10, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 25, 2017Group: Refinement description / Category: software
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
Revision 1.5Apr 3, 2024Group: Refinement description / Category: 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
D: Corticosteroid 11-beta-dehydrogenase isozyme 1
E: Corticosteroid 11-beta-dehydrogenase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)129,66512
Polymers125,3854
Non-polymers4,2798
Water4,234235
1
A: Corticosteroid 11-beta-dehydrogenase isozyme 1
B: Corticosteroid 11-beta-dehydrogenase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,8326
Polymers62,6932
Non-polymers2,1404
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7950 Å2
ΔGint-63 kcal/mol
Surface area21730 Å2
MethodPISA
2
D: Corticosteroid 11-beta-dehydrogenase isozyme 1
E: Corticosteroid 11-beta-dehydrogenase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,8326
Polymers62,6932
Non-polymers2,1404
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7610 Å2
ΔGint-60 kcal/mol
Surface area21330 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.500, 94.300, 167.000
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
Corticosteroid 11-beta-dehydrogenase isozyme 1 / E.C.1.1.1.146 / 11-DH / 11-beta-hydroxysteroid dehydrogenase 1 / 11-beta-HSD1


Mass: 31346.348 Da / Num. of mol.: 4 / Fragment: 11-BETA HYDROXYSTEROID DEHYDROGENASE / Mutation: L262R,F278E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSD11B1, HSD11, HSD11L / Plasmid: PET28 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
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-311 / (3,3-dimethylpiperidin-1-yl)(6-(3-fluoro-4-methylphenyl)pyridin-2-yl)methanone


Mass: 326.408 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H23FN2O
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 235 / 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: 2.34 Å3/Da / Density % sol: 47.42 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.3
Details: 200 mM potassium formate, pH 7.3, 22% (W/V) PEG3350, 1.5 mM Zwittergent 3-12, vapor diffusion, hanging drop, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU SATURN 92 / Detector: CCD / Date: Dec 11, 2006 / Details: MICROMAX CONFOCAL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.35→50 Å / Num. all: 44883 / Num. obs: 44565 / % possible obs: 89.6 % / Observed criterion σ(I): 0 / Redundancy: 4.3 % / Biso Wilson estimate: 40.794 Å2 / Rmerge(I) obs: 0.038 / Net I/σ(I): 28.7
Reflection shellResolution: 2.35→2.43 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.132 / Mean I/σ(I) obs: 9.1 / Num. unique all: 3935 / % possible all: 80

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
TNTrefinement
PDB_EXTRACT3.004data extraction
HKL-2000(DENZO)data reduction
HKL-2000(SCALEPACK)data scaling
AMoREphasing
BUSTER-TNT2.1.1refinement
RefinementMethod to determine structure: molecular replacement
Starting model: 11BHSD/LIGAND

Resolution: 2.35→50 Å / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2299 1061 2.38 %RANDOM
Rwork0.1872 ---
all0.194 44883 --
obs0.1883 44565 89.34 %-
Displacement parametersBiso mean: 32.5 Å2
Baniso -1Baniso -2Baniso -3
1-9.5111182 Å20 Å20 Å2
2---4.00744959 Å20 Å2
3----5.50366862 Å2
Refinement stepCycle: LAST / Resolution: 2.35→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8252 0 288 235 8775
Refine LS restraints
Refine-IDTypeDev idealNumberWeight
X-RAY DIFFRACTIONt_bond_d0.0186982
X-RAY DIFFRACTIONt_angle_deg1.206117622
X-RAY DIFFRACTIONt_dihedral_angle_d20.29317620
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle0.45436
X-RAY DIFFRACTIONt_trig_c_planes0.011942
X-RAY DIFFRACTIONt_gen_planes0.01612555
X-RAY DIFFRACTIONt_it1.22869820
X-RAY DIFFRACTIONt_nbd0.05815
LS refinement shellResolution: 2.35→2.49 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.258 132 2.01 %
Rwork0.2184 6434 -
all0.2192 6566 -
obs--89.34 %

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