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- PDB-4c7k: 11b-Hydroxysteroid Dehydrogenase Type I in complex with inhibitor -

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Basic information

Entry
Database: PDB / ID: 4c7k
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


cortisol dehydrogenase (NADP+) activity / 11-beta-hydroxysteroid dehydrogenase (NADP+) activity / 11beta-hydroxysteroid dehydrogenase / 7beta-hydroxysteroid dehydrogenase (NADP+) / 7-beta-hydroxysteroid dehydrogenase (NADP+) activity / Glucocorticoid biosynthesis / steroid catabolic process / Prednisone ADME / steroid binding / lung development ...cortisol dehydrogenase (NADP+) activity / 11-beta-hydroxysteroid dehydrogenase (NADP+) activity / 11beta-hydroxysteroid dehydrogenase / 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-DZL / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 11-beta-hydroxysteroid dehydrogenase 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.91 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 1.0Mar 5, 2014Provider: repository / Type: Initial release
Revision 1.1Jun 28, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.2Dec 20, 2023Group: 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 / pdbx_initial_refinement_model / 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)122,69711
Polymers118,5944
Non-polymers4,1037
Water13,385743
1
A: CORTICOSTEROID 11-BETA-DEHYDROGENASE ISOZYME 1
B: CORTICOSTEROID 11-BETA-DEHYDROGENASE ISOZYME 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,5376
Polymers59,2972
Non-polymers2,2404
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7290 Å2
ΔGint-48.7 kcal/mol
Surface area20300 Å2
MethodPISA
2
C: CORTICOSTEROID 11-BETA-DEHYDROGENASE ISOZYME 1
hetero molecules

D: CORTICOSTEROID 11-BETA-DEHYDROGENASE ISOZYME 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,1605
Polymers59,2972
Non-polymers1,8633
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x+1/2,-y+1/2,-z1
Buried area7220 Å2
ΔGint-47.3 kcal/mol
Surface area20840 Å2
MethodPISA
3
D: CORTICOSTEROID 11-BETA-DEHYDROGENASE ISOZYME 1
hetero molecules

C: CORTICOSTEROID 11-BETA-DEHYDROGENASE ISOZYME 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,1605
Polymers59,2972
Non-polymers1,8633
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_455x-1/2,-y+1/2,-z1
Buried area7220 Å2
ΔGint-47.3 kcal/mol
Surface area20840 Å2
MethodPISA
Unit cell
Length a, b, c (Å)99.330, 99.250, 99.940
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-DZL / 2-ethyl-N-[(1S,3R)-5-oxidanyl-2-adamantyl]-4-[(2R)-oxolan-2-yl]-1,3-thiazole-5-carboxamide


Mass: 376.513 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C20H28N2O3S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 743 / 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+ SUPERBRIGHT / Wavelength: 1.54
DetectorType: RIGAKU HTC / Detector: IMAGE PLATE / Date: Feb 22, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.91→49.63 Å / Num. obs: 74883 / % possible obs: 96.1 % / Observed criterion σ(I): 2 / Redundancy: 7.1 % / Biso Wilson estimate: 20.14 Å2 / Rmerge(I) obs: 0.09 / Net I/σ(I): 20.4
Reflection shellResolution: 1.91→1.96 Å / Redundancy: 6.2 % / Rmerge(I) obs: 0.44 / Mean I/σ(I) obs: 4.9 / % possible all: 87.9

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
XDSdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4BB5

4bb5


Resolution: 1.91→49.63 Å / Cor.coef. Fo:Fc: 0.9055 / Cor.coef. Fo:Fc free: 0.8536 / SU R Cruickshank DPI: 0.223 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.236 / SU Rfree Blow DPI: 0.198 / SU Rfree Cruickshank DPI: 0.194
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.2905 3737 5.04 %RANDOM
Rwork0.2399 ---
obs0.2424 74088 95.98 %-
Displacement parametersBiso mean: 29.16 Å2
Baniso -1Baniso -2Baniso -3
1--0.0549 Å20 Å20 Å2
2---0.1703 Å20 Å2
3---0.2253 Å2
Refine analyzeLuzzati coordinate error obs: 0.332 Å
Refinement stepCycle: LAST / Resolution: 1.91→49.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7895 0 270 743 8908
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.018320HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1211286HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2897SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes152HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1203HARMONIC5
X-RAY DIFFRACTIONt_it8320HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.91
X-RAY DIFFRACTIONt_other_torsion18.86
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1118SEMIHARMONIC5
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_contact10695SEMIHARMONIC4
LS refinement shellResolution: 1.91→1.96 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.5563 249 5.02 %
Rwork0.4788 4715 -
all0.4826 4964 -
obs--95.98 %

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