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- PDB-4c7j: 11b-Hydroxysteroid Dehydrogenase Type I in complex with inhibitor -

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Basic information

Entry
Database: PDB / ID: 4c7j
Title11b-Hydroxysteroid Dehydrogenase Type I in complex with inhibitor
ComponentsCORTICOSTEROID 11-BETA-DEHYDROGENASE ISOZYME 1
KeywordsOXIDOREDUCTASE / CNS PENETRATION / STRUCTURE-BASED DESIGN
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-4YQ / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 11-beta-hydroxysteroid dehydrogenase 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.16 Å
AuthorsGoldberg, F.W. / Dossetter, A.G. / Scott, J.S. / Robb, G.R. / Boyd, S. / Groombridge, S.D. / Kemmitt, P.D. / Sjogren, T. / Morentin Gutierrez, P. / de Schoolmeester, J. ...Goldberg, F.W. / Dossetter, A.G. / Scott, J.S. / Robb, G.R. / Boyd, S. / Groombridge, S.D. / Kemmitt, P.D. / Sjogren, T. / Morentin Gutierrez, P. / de Schoolmeester, J. / Swales, J.G. / Turnbull, A.V. / Wild, M.J.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Optimization of Brain Penetrant 11Beta-Hydroxysteroid Dehydrogenase Type I Inhibitors and in Vivo Testing in Diet- Induced Obese Mice.
Authors: Goldberg, F.W. / Dossetter, A.G. / Scott, J.S. / Robb, G.R. / Boyd, S. / Groombridge, S.D. / Kemmitt, P.D. / Sjogren, T. / Gutierrez, P.M. / Deschoolmeester, J. / Swales, J.G. / Turnbull, A.V. / Wild, M.J.
History
DepositionSep 23, 2013Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 3, 2014Provider: repository / Type: Initial release
Revision 1.1Apr 4, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.2May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / 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_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
C: CORTICOSTEROID 11-BETA-DEHYDROGENASE ISOZYME 1
D: CORTICOSTEROID 11-BETA-DEHYDROGENASE ISOZYME 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)123,08112
Polymers118,5944
Non-polymers4,4888
Water10,899605
1
A: CORTICOSTEROID 11-BETA-DEHYDROGENASE ISOZYME 1
B: CORTICOSTEROID 11-BETA-DEHYDROGENASE ISOZYME 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,5416
Polymers59,2972
Non-polymers2,2444
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8150 Å2
ΔGint-52 kcal/mol
Surface area20130 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)61,5416
Polymers59,2972
Non-polymers2,2444
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7380 Å2
ΔGint-50.7 kcal/mol
Surface area19660 Å2
MethodPISA
Unit cell
Length a, b, c (Å)95.686, 98.435, 99.112
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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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: 29648.395 Da / Num. of mol.: 4 / Fragment: RESIDUES 24-292 / Mutation: YES
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


Mass: 743.405 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#3: Chemical
ChemComp-4YQ / 4-cyclopropyl-2-(2-hydroxyethyloxy)-N-[(1S,3R)-5-oxidanyl-2-adamantyl]-1,3-thiazole-5-carboxamide


Mass: 378.486 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C19H26N2O4S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 605 / 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: 1.9 Å3/Da / Density % sol: 36 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ / Wavelength: 1.54
DetectorType: RAXIS HTC / Detector: IMAGE PLATE / Date: May 17, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.16→33.04 Å / Num. obs: 50932 / % possible obs: 100 % / Observed criterion σ(I): 2 / Redundancy: 3.9 % / Rmerge(I) obs: 0.12 / Net I/σ(I): 9.7
Reflection shellResolution: 2.16→2.22 Å / Redundancy: 3.9 % / Rmerge(I) obs: 0.55 / Mean I/σ(I) obs: 2.4 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.5.0109refinement
MOSFLMdata reduction
XDSdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.16→68.61 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.898 / SU B: 6.3 / SU ML: 0.16 / Cross valid method: THROUGHOUT / ESU R: 0.34 / ESU R Free: 0.23 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.23956 2478 5 %RANDOM
Rwork0.17388 ---
obs0.17718 46877 97 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 21.822 Å2
Baniso -1Baniso -2Baniso -3
1-0.18 Å20 Å20 Å2
2---0.08 Å20 Å2
3----0.1 Å2
Refinement stepCycle: LAST / Resolution: 2.16→68.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7952 0 296 605 8853
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.028416
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.646211422
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1851033
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.29123.75309
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.03151474
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.5761541
X-RAY DIFFRACTIONr_chiral_restr0.1110.21348
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.026000
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_it1.0121.55131
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.92928248
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.03533285
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it4.9734.53161
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
LS refinement shellResolution: 2.16→2.216 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.306 181 -
Rwork0.229 3245 -
obs--92.17 %

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