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Entry
Database: PDB / ID: 4bb6
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 / BHSD
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-HD1 / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 11-beta-hydroxysteroid dehydrogenase 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.55 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
Revision 1.2May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / struct_ncs_dom_lim / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,3837
Polymers64,9722
Non-polymers2,4125
Water25214
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7610 Å2
ΔGint-60.4 kcal/mol
Surface area21170 Å2
MethodPISA
Unit cell
Length a, b, c (Å)108.651, 108.651, 135.771
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number152
Space group name H-MP3121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: GLU / Beg label comp-ID: GLU / Refine code: 5

Dom-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
1ASNASNAA26 - 29126 - 291
2SERSERBB26 - 28326 - 283

NCS oper: (Code: given
Matrix: (0.2147, 0.7438, 0.6329), (0.74, -0.5468, 0.3916), (0.6374, 0.3843, -0.6679)
Vector: -64.52, 76.44, 33.82)

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Components

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


Mass: 32485.834 Da / Num. of mol.: 2
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.: 2 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#3: Chemical ChemComp-HD1 / 6-(4-methylpiperazin-1-yl)-N-[(1R,3S)-5-oxidanyl-2-adamantyl]-2-propylsulfanyl-pyridine-3-carboxamide


Mass: 444.633 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H36N4O2S
#4: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 14 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 4.02 Å3/Da / Density % sol: 69.4 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Type: ESRF / Wavelength: 1.072
DetectorDate: Jan 30, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.072 Å / Relative weight: 1
ReflectionResolution: 2.55→21.3 Å / Num. obs: 28890 / % possible obs: 99.6 % / Observed criterion σ(I): 1 / Redundancy: 10.1 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 10.8
Reflection shellResolution: 2.55→2.64 Å / Redundancy: 6.4 % / Rmerge(I) obs: 0.53 / Mean I/σ(I) obs: 2.1 / % possible all: 96.2

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Processing

SoftwareName: REFMAC / Version: 5.4.0061 / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.55→21.32 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.936 / SU B: 21.303 / SU ML: 0.203 / Cross valid method: THROUGHOUT / ESU R: 0.353 / ESU R Free: 0.274 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.27648 1533 5 %RANDOM
Rwork0.23 ---
obs0.23 28890 99.12 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 65.167 Å2
Baniso -1Baniso -2Baniso -3
1-2.06 Å21.03 Å20 Å2
2--2.06 Å20 Å2
3----3.09 Å2
Refinement stepCycle: LAST / Resolution: 2.55→21.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4010 0 159 14 4183
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0224249
X-RAY DIFFRACTIONr_bond_other_d0.0030.022806
X-RAY DIFFRACTIONr_angle_refined_deg1.5811.9785766
X-RAY DIFFRACTIONr_angle_other_deg0.9932.9986758
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5285522
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.50723.701154
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.33315740
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.6611521
X-RAY DIFFRACTIONr_chiral_restr0.0890.2683
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.024545
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02798
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_it0.6051.52594
X-RAY DIFFRACTIONr_mcbond_other0.1291.51070
X-RAY DIFFRACTIONr_mcangle_it1.16424168
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.80231655
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.8564.51598
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Refine-ID: X-RAY DIFFRACTION

Dom-IDAuth asym-IDNumberTypeRms dev position (Å)Weight position
1A1525medium positional0.390.5
2B1525medium positional0.390.5
1A1785loose positional0.665
2B1785loose positional0.665
1A1525medium thermal0.482
2B1525medium thermal0.482
1A1785loose thermal0.610
2B1785loose thermal0.610
LS refinement shellResolution: 2.55→2.615 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.418 112 -
Rwork0.362 2010 -
obs--95.59 %
Refinement TLS params.Method: refined / Origin x: -7.5256 Å / Origin y: 53.5477 Å / Origin z: 30.1178 Å
111213212223313233
T-0.2098 Å2-0.1285 Å2-0.0197 Å2--0.0447 Å2-0.0442 Å2---0.1434 Å2
L1.0124 °2-0.4381 °20.3157 °2-1.498 °2-0.5001 °2--2.2821 °2
S0.0782 Å °-0.0438 Å °-0.0135 Å °0.0408 Å °0.1079 Å °-0.0283 Å °-0.0567 Å °0.0919 Å °-0.1861 Å °

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