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- PDB-4p38: Human 11beta-Hydroxysteroid Dehydrogenase Type 1 in complex with ... -

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Basic information

Entry
Database: PDB / ID: 4p38
TitleHuman 11beta-Hydroxysteroid Dehydrogenase Type 1 in complex with AZD8329
ComponentsCorticosteroid 11-beta-dehydrogenase isozyme 1
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / Alpha Beta / Rossmann fold / NADP / Oxidoreductase-Oxidoreductase inhibitor complex
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-21T / Chem-NDP / 11-beta-hydroxysteroid dehydrogenase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsOgg, D. / Hargreaves, D. / Gerhardt, S.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Novel acidic 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) inhibitor with reduced acyl glucuronide liability: the discovery of 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1- ...Title: Novel acidic 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) inhibitor with reduced acyl glucuronide liability: the discovery of 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid (AZD8329).
Authors: Scott, J.S. / deSchoolmeester, J. / Kilgour, E. / Mayers, R.M. / Packer, M.J. / Hargreaves, D. / Gerhardt, S. / Ogg, D.J. / Rees, A. / Selmi, N. / Stocker, A. / Swales, J.G. / Whittamore, P.R.
History
DepositionMar 6, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 30, 2014Provider: repository / Type: Initial release
Revision 1.1Nov 12, 2014Group: Structure summary
Revision 1.2Nov 1, 2017Group: Author supporting evidence / Database references ...Author supporting evidence / Database references / Derived calculations / Other / Refinement description / Source and taxonomy
Category: citation / entity_src_gen ...citation / entity_src_gen / pdbx_database_status / pdbx_struct_assembly / pdbx_struct_assembly_auth_evidence / pdbx_struct_oper_list / software
Item: _citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag ..._citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Feb 28, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_related / refine_hist
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_related.content_type / _refine_hist.number_atoms_solvent / _refine_hist.number_atoms_total / _refine_hist.pdbx_number_atoms_ligand / _refine_hist.pdbx_number_atoms_nucleic_acid
Remark 0This is a pdbchk output, created Thu Oct 18 11:43:16 2012 on host: ukapdwlx049. Original file: ...This is a pdbchk output, created Thu Oct 18 11:43:16 2012 on host: ukapdwlx049. Original file: /xtal/work/bhsd/AZ12782812/deposit/bhsd-AZ12782812_fi

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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)60,8398
Polymers58,4342
Non-polymers2,4056
Water52229
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8490 Å2
ΔGint-91 kcal/mol
Surface area20570 Å2
MethodPISA
2
A: Corticosteroid 11-beta-dehydrogenase isozyme 1
B: Corticosteroid 11-beta-dehydrogenase isozyme 1
hetero molecules

A: Corticosteroid 11-beta-dehydrogenase isozyme 1
B: Corticosteroid 11-beta-dehydrogenase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)121,67716
Polymers116,8684
Non-polymers4,81012
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation6_555-x,-x+y,-z+1/31
Buried area19400 Å2
ΔGint-202 kcal/mol
Surface area38730 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.516, 103.516, 134.780
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number152
Space group name H-MP3121
DetailsGel filtration confirms the dimerization of the protein in solution

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Components

#1: Protein Corticosteroid 11-beta-dehydrogenase isozyme 1 / 11-beta-hydroxysteroid dehydrogenase 1 / 11-beta-HSD1


Mass: 29216.912 Da / Num. of mol.: 2 / Mutation: M179L, L262R, C272S, F278E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSD11B1, HSD11, HSD11L / Production host: Escherichia coli (E. coli)
References: UniProt: P28845, 11beta-hydroxysteroid dehydrogenase
#2: Chemical ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE


Mass: 745.421 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#3: Chemical ChemComp-21T / 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid


Mass: 421.532 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H31N3O3
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 29 / 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: 3.57 Å3/Da / Density % sol: 65.52 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 42% PEG400, 100 mM Tris-HCl pH 8.5 and 2 mM compound

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E DW / Wavelength: 1.514 Å
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Apr 22, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.514 Å / Relative weight: 1
ReflectionResolution: 2.8→30.27 Å / Num. obs: 20969 / % possible obs: 99.6 % / Redundancy: 6.9 % / Biso Wilson estimate: 103.69 Å2 / Rmerge(I) obs: 0.111 / Net I/σ(I): 8.5
Reflection shellResolution: 2.8→2.9 Å / Redundancy: 6.9 % / Rmerge(I) obs: 0.54 / Mean I/σ(I) obs: 1.9 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.2refinement
d*TREK9.9Ldata scaling
CrystalCleardata collection
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.8→30.27 Å / Cor.coef. Fo:Fc: 0.9322 / Cor.coef. Fo:Fc free: 0.9165 / SU R Cruickshank DPI: 0.682 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.668 / SU Rfree Blow DPI: 0.34 / SU Rfree Cruickshank DPI: 0.346
RfactorNum. reflection% reflectionSelection details
Rfree0.2722 1062 5.11 %RANDOM
Rwork0.2268 ---
obs0.229 20763 98.68 %-
Displacement parametersBiso mean: 75.53 Å2
Baniso -1Baniso -2Baniso -3
1--8.9291 Å20 Å20 Å2
2---8.9291 Å20 Å2
3---17.8581 Å2
Refine analyzeLuzzati coordinate error obs: 0.505 Å
Refinement stepCycle: 1 / Resolution: 2.8→30.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4077 0 160 29 4266
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014323HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.275873HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1501SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes81HARMONIC2
X-RAY DIFFRACTIONt_gen_planes666HARMONIC5
X-RAY DIFFRACTIONt_it4323HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.01
X-RAY DIFFRACTIONt_other_torsion20.13
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion568SEMIHARMONIC5
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_contact5144SEMIHARMONIC4
LS refinement shellResolution: 2.8→2.95 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.314 146 4.89 %
Rwork0.2776 2840 -
all0.2794 2986 -
obs--98.68 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.42280.02830.14671.7259-0.65263.19920.01760.03070.25230.05030.0086-0.0052-0.5638-0.1337-0.0262-0.1326-0.04460.0091-0.17090.0303-0.1187-13.078665.282530.4737
21.2478-0.27910.75612.0845-0.40823.06820.1063-0.0373-0.2163-0.0940.0245-0.02330.70630.2255-0.1308-0.1175-0.0358-0.0835-0.13360.0031-0.1738-4.301338.124738.8979
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

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