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Entry
Database: PDB / ID: 4bb5
TitleFree-Wilson and Structural Approaches to Co-optimising Human and Rodent Isoform Potency for 11b-Hydroxysteroid Dehydrogenase Type 1 11b-HSD1 Inhibitors
ComponentsCORTICOSTEROID 11-BETA-DEHYDROGENASE ISOZYME 1
KeywordsOXIDOREDUCTASE
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-HD2 / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 11-beta-hydroxysteroid dehydrogenase 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsGoldberg, F.W. / Leach, A.G. / Scott, J.S. / Snelson, W.L. / Groombridge, S.D. / Donald, C.S. / Bennett, S.N.L. / Bodin, C. / Morentin Gutierrez, P. / Gyte, A.C.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Free-Wilson and Structural Approaches to Co-Optimising Human and Rodent Isoform Potency for 11Beta-Hydroxysteroid Dehydrogenase Type 1 (11Beta-Hsd1) Inhibitors
Authors: Goldberg, F.W. / Leach, A.G. / Scott, J.S. / Snelson, W.L. / Groombridge, S.D. / Donald, C.S. / Bennett, S.N.L. / Bodin, C. / Morentin Gutierrez, P. / Gyte, A.C.
History
DepositionSep 20, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 28, 2012Provider: repository / Type: Initial release
Revision 1.1Dec 26, 2012Group: Database references / Refinement description

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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)134,40312
Polymers129,7234
Non-polymers4,6808
Water5,621312
1
A: CORTICOSTEROID 11-BETA-DEHYDROGENASE ISOZYME 1
B: CORTICOSTEROID 11-BETA-DEHYDROGENASE ISOZYME 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,2026
Polymers64,8622
Non-polymers2,3404
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8460 Å2
ΔGint-56.2 kcal/mol
Surface area20140 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)67,2026
Polymers64,8622
Non-polymers2,3404
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7660 Å2
ΔGint-49.2 kcal/mol
Surface area19800 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.781, 132.482, 154.819
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(-0.661, -0.042, 0.75), (-0.044, -0.995, -0.095), (0.75, -0.096, 0.655)45.85834, -8.10008, -21.26853
2given(1, 0.022, -0.013), (0.02, -0.989, -0.149), (-0.016, 0.148, -0.989)-17.43429, -2.66651, -98.71673
3given(-0.663, -0.083, 0.744), (-0.069, 0.996, 0.05), (-0.745, -0.018, -0.667)28.60017, 10.33007, -79.23773

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Components

#1: Protein
CORTICOSTEROID 11-BETA-DEHYDROGENASE ISOZYME 1 / 11B-HYDROXYSTEROID DEHYDROGENASE TYPE 1 / BHSD / 11-BETA-HYDROXYSTEROID DEHYDROGENASE 1 / 11-DH / 11-BETA-HSD1


Mass: 32430.818 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli)
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-HD2 / 4-cyclopentyl-N-[(1S,3R)-5-oxidanyl-2-adamantyl]-2-[[(3S)-oxolan-3-yl]amino]pyrimidine-5-carboxamide


Mass: 426.552 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C24H34N4O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 312 / 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: 2.2 Å3/Da / Density % sol: 44 % / Description: NONE
Crystal growpH: 7 / Details: pH 7

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1.072
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Nov 10, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.072 Å / Relative weight: 1
ReflectionResolution: 2.1→48.09 Å / Num. obs: 59410 / % possible obs: 99.6 % / Observed criterion σ(I): 1 / Redundancy: 6.8 % / Biso Wilson estimate: 23.89 Å2 / Rmerge(I) obs: 0.16 / Net I/σ(I): 10.2
Reflection shellResolution: 2.1→2.15 Å / Redundancy: 3.2 % / Rmerge(I) obs: 0.76 / Mean I/σ(I) obs: 3.2 / % possible all: 98.7

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Processing

Software
NameVersionClassification
BUSTER2.11.1refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→35 Å / Cor.coef. Fo:Fc: 0.9313 / Cor.coef. Fo:Fc free: 0.9034 / SU R Cruickshank DPI: 0.284 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.294 / SU Rfree Blow DPI: 0.198 / SU Rfree Cruickshank DPI: 0.198
Details: NUMBER OF LIBRARIES USED: 9 REFINEMENT NOTE 1: IDEAL-DIST CONTACT TERM CONTACT SETUP ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY. NCS REPRESENTATION: RESTRAINT LSSR (- AUTONCS)
RfactorNum. reflection% reflectionSelection details
Rfree0.2204 2607 5.04 %RANDOM
Rwork0.1825 ---
obs0.1843 51750 99.64 %-
Displacement parametersBiso mean: 25.57 Å2
Baniso -1Baniso -2Baniso -3
1--2.7998 Å20 Å20 Å2
2--0.206 Å20 Å2
3---2.5937 Å2
Refine analyzeLuzzati coordinate error obs: 0.242 Å
Refinement stepCycle: LAST / Resolution: 2.2→35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8013 0 316 312 8641
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.018496HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1511524HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2903SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes185HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1269HARMONIC5
X-RAY DIFFRACTIONt_it8496HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.25
X-RAY DIFFRACTIONt_other_torsion18.09
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1134SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact10490SEMIHARMONIC4
LS refinement shellResolution: 2.2→2.26 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.243 165 4.43 %
Rwork0.2295 3559 -
all0.2302 3724 -
obs--99.64 %

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