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- PDB-4nmh: 11-beta-HSD1 in complex with a 3,3-Di-methyl-azetidin-2-one -

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Basic information

Entry
Database: PDB / ID: 4nmh
Title11-beta-HSD1 in complex with a 3,3-Di-methyl-azetidin-2-one
ComponentsCorticosteroid 11-beta-dehydrogenase isozyme 1
Keywordsoxidoreductase/oxidoreductase INHIBITOR / NAD(P)-binding Rossmann-fold domains / OXIDOREDUCTASE / oxidoreductase-oxidoreductase INHIBITOR complex
Function / homology
Function and homology information


mineralocorticoid metabolic process / Glucocorticoid biosynthesis / glucocorticoid catabolic process / regulation of pentose-phosphate shunt / glucocorticoid biosynthetic process / 11beta-hydroxysteroid dehydrogenase / 11-beta-hydroxysteroid dehydrogenase (NADP+) activity / cortisol dehydrogenase activity / 7beta-hydroxysteroid dehydrogenase (NADP+) / 7-beta-hydroxysteroid dehydrogenase (NADP+) activity ...mineralocorticoid metabolic process / Glucocorticoid biosynthesis / glucocorticoid catabolic process / regulation of pentose-phosphate shunt / glucocorticoid biosynthetic process / 11beta-hydroxysteroid dehydrogenase / 11-beta-hydroxysteroid dehydrogenase (NADP+) activity / cortisol dehydrogenase activity / 7beta-hydroxysteroid dehydrogenase (NADP+) / 7-beta-hydroxysteroid dehydrogenase (NADP+) activity / Prednisone ADME / steroid catabolic process / steroid binding / lung development / apical part of cell / NADP binding / nuclear membrane / intracellular membrane-bounded organelle / endoplasmic reticulum membrane / protein homodimerization activity
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-2KG / Chem-NDP / 11-beta-hydroxysteroid dehydrogenase 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsMcCoull, W. / Augustin, M. / Blake, C. / Ertan, A. / Kilgour, E.K. / Krapp, S. / Moore, J.E. / Newcombe, N.J. / Packer, M.J. / Rees, A. ...McCoull, W. / Augustin, M. / Blake, C. / Ertan, A. / Kilgour, E.K. / Krapp, S. / Moore, J.E. / Newcombe, N.J. / Packer, M.J. / Rees, A. / Revill, J. / Scott, J.S. / Selmi, N. / Gerhardt, S. / Ogg, D.J. / Steinbacher, S. / Whittamore, P.R.O.
CitationJournal: TO BE PUBLISHED
Title: Identification and optimisation of 3,3-dimethyl-azetidin-2-ones as potent and selective inhibitors of 11 beta-hydroxysteroid dehydrogenase type 1 (11-beta-HSD1)
Authors: McCoull, W. / Augustin, M. / Blake, C. / Ertan, A. / Kilgour, E.K. / Krapp, S. / Moore, J.E. / Newcombe, N.J. / Packer, M.J. / Rees, A. / Revill, J. / Scott, J.S. / Selmi, N. / Gerhardt, S. ...Authors: McCoull, W. / Augustin, M. / Blake, C. / Ertan, A. / Kilgour, E.K. / Krapp, S. / Moore, J.E. / Newcombe, N.J. / Packer, M.J. / Rees, A. / Revill, J. / Scott, J.S. / Selmi, N. / Gerhardt, S. / Ogg, D.J. / Steinbacher, S. / Whittamore, P.R.O.
History
DepositionNov 15, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 26, 2014Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ncs_dom_lim / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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_ref_seq_dif.details / _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)136,61618
Polymers131,6204
Non-polymers4,99614
Water59433
1
A: Corticosteroid 11-beta-dehydrogenase isozyme 1
B: Corticosteroid 11-beta-dehydrogenase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,3089
Polymers65,8102
Non-polymers2,4987
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8470 Å2
ΔGint-114 kcal/mol
Surface area21070 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)68,3089
Polymers65,8102
Non-polymers2,4987
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8490 Å2
ΔGint-114 kcal/mol
Surface area21120 Å2
MethodPISA
Unit cell
Length a, b, c (Å)96.132, 70.842, 95.653
Angle α, β, γ (deg.)90.00, 91.67, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21D
12B
22C

NCS domain segments:

Component-ID: 1 / Beg auth comp-ID: GLU / Beg label comp-ID: GLU / End auth comp-ID: ASN / End label comp-ID: ASN / Refine code: 2 / Auth seq-ID: 30 - 285 / Label seq-ID: 34 - 289

Dom-IDEns-IDAuth asym-IDLabel asym-ID
11AA
21DD
12BB
22CC

NCS ensembles :
ID
1
2

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Components

#1: Protein
Corticosteroid 11-beta-dehydrogenase isozyme 1 / 11-beta-hydroxysteroid dehydrogenase 1 / 11-DH / 11-beta-HSD1 / 11beta-HSD1A


Mass: 32905.098 Da / Num. of mol.: 4 / Mutation: M175V, Q177Y, I180V
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Hsd11b1, Hsd11 / Production host: Escherichia coli (E. coli)
References: UniProt: P50172, 11beta-hydroxysteroid dehydrogenase
#2: Chemical
ChemComp-2KG / (4S)-4-(2-methoxyphenyl)-3,3-dimethyl-1-[3-(methylsulfonyl)phenyl]azetidin-2-one


Mass: 359.439 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C19H21NO4S
#3: Chemical
ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Nicotinamide adenine dinucleotide phosphate


Mass: 745.421 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#4: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 33 / 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: 2.47 Å3/Da / Density % sol: 50.27 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 1.9 M ammonium sulphate, 0.1 M citrate at pH 5.5, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 1.037 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Aug 3, 2006 / Details: toroidal mirror
RadiationMonochromator: high resolution Si(311) cut and a lower resolution Si(111) cut
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.037 Å / Relative weight: 1
ReflectionResolution: 2.9→96.23 Å / Num. all: 25245 / Num. obs: 25245 / % possible obs: 87.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 2.8 % / Biso Wilson estimate: 40.3 Å2 / Rmerge(I) obs: 0.154 / Net I/σ(I): 3.9
Reflection shellResolution: 2.9→3.06 Å / Redundancy: 2.6 % / Rmerge(I) obs: 0.446 / Mean I/σ(I) obs: 1.4 / Num. unique all: 3360 / % possible all: 80.8

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
MOLREPphasing
REFMAC5.2.0019refinement
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.9→96.23 Å / Cor.coef. Fo:Fc: 0.913 / Cor.coef. Fo:Fc free: 0.877 / SU B: 15.504 / SU ML: 0.288 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R Free: 0.462 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25139 1294 5.1 %RANDOM
Rwork0.19867 ---
all0.20132 25228 --
obs0.20132 25228 87.6 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 21.177 Å2
Baniso -1Baniso -2Baniso -3
1-0.64 Å20 Å2-2.69 Å2
2---2.53 Å20 Å2
3---1.73 Å2
Refinement stepCycle: LAST / Resolution: 2.9→96.23 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8142 0 322 33 8497
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0228602
X-RAY DIFFRACTIONr_bond_other_d0.0010.025748
X-RAY DIFFRACTIONr_angle_refined_deg0.9022.02611658
X-RAY DIFFRACTIONr_angle_other_deg1.592314109
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.85851056
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.28823.851296
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.65151545
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.0091537
X-RAY DIFFRACTIONr_chiral_restr0.0480.21355
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.029149
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021632
X-RAY DIFFRACTIONr_nbd_refined0.1810.21929
X-RAY DIFFRACTIONr_nbd_other0.1730.25638
X-RAY DIFFRACTIONr_nbtor_refined0.1720.24231
X-RAY DIFFRACTIONr_nbtor_other0.0760.24209
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1180.2211
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1390.219
X-RAY DIFFRACTIONr_symmetry_vdw_other0.130.239
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.10.23
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.95626843
X-RAY DIFFRACTIONr_mcbond_other0.02722158
X-RAY DIFFRACTIONr_mcangle_it1.09738462
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.74643897
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.57663188
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

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

Ens-IDAuth asym-IDNumberTypeRms dev position (Å)Weight position
1A1504tight positional0.010.05
2B1510tight positional0.010.05
1A1768medium positional0.360.5
2B1785medium positional0.370.5
1A1504tight thermal0.020.5
2B1510tight thermal0.020.5
1A1768medium thermal0.152
2B1785medium thermal0.152
LS refinement shellResolution: 2.9→2.975 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.368 99 -
Rwork0.285 1600 -
obs-1699 80.56 %

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