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- PDB-4ijv: Crystal structure of 11b-HSD1 double mutant (L262R, F278E) in com... -

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Basic information

Entry
Database: PDB / ID: 4ijv
TitleCrystal structure of 11b-HSD1 double mutant (L262R, F278E) in complex with 3-[1-(4-chlorophenyl)cyclopropyl]-8-(2-fluorophenoxy)[1,2,4]triazolo[4,3-a]pyridine
ComponentsCorticosteroid 11-beta-dehydrogenase isozyme 1
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / 11b-HSD1 / SDR / dehydrogenase / hydroxysteroid / inhibitor / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
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-1EN / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 11-beta-hydroxysteroid dehydrogenase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.35 Å
AuthorsSheriff, S.
CitationJournal: ACS Med Chem Lett / Year: 2014
Title: Optimization of 1,2,4-Triazolopyridines as Inhibitors of Human 11 beta-Hydroxysteroid Dehydrogenase Type 1 (11 beta-HSD-1).
Authors: Li, J. / Kennedy, L.J. / Wang, H. / Li, J.J. / Walker, S.J. / Hong, Z. / O'Connor, S.P. / Nayeem, A. / Camac, D.M. / Morin, P.E. / Sheriff, S. / Wang, M. / Harper, T. / Golla, R. / Seethala, ...Authors: Li, J. / Kennedy, L.J. / Wang, H. / Li, J.J. / Walker, S.J. / Hong, Z. / O'Connor, S.P. / Nayeem, A. / Camac, D.M. / Morin, P.E. / Sheriff, S. / Wang, M. / Harper, T. / Golla, R. / Seethala, R. / Harrity, T. / Ponticiello, R.P. / Morgan, N.N. / Taylor, J.R. / Zebo, R. / Gordon, D.A. / Robl, J.A.
History
DepositionDec 23, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 11, 2014Provider: repository / Type: Initial release
Revision 1.1Aug 6, 2014Group: Database references
Revision 1.2Sep 20, 2023Group: 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 / pdbx_initial_refinement_model / 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_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
D: Corticosteroid 11-beta-dehydrogenase isozyme 1
E: Corticosteroid 11-beta-dehydrogenase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)129,87812
Polymers125,3854
Non-polymers4,4938
Water5,621312
1
A: Corticosteroid 11-beta-dehydrogenase isozyme 1
B: Corticosteroid 11-beta-dehydrogenase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,9396
Polymers62,6932
Non-polymers2,2464
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8390 Å2
ΔGint-64 kcal/mol
Surface area21720 Å2
MethodPISA
2
D: Corticosteroid 11-beta-dehydrogenase isozyme 1
E: Corticosteroid 11-beta-dehydrogenase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,9396
Polymers62,6932
Non-polymers2,2464
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8050 Å2
ΔGint-60 kcal/mol
Surface area21530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.400, 94.000, 167.800
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


Mass: 31346.348 Da / Num. of mol.: 4 / Mutation: L262R, F278E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSD11B1, HSD11, HSD11L / Plasmid: PET28 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
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-1EN / 3-[1-(4-chlorophenyl)cyclopropyl]-8-(2-fluorophenoxy)[1,2,4]triazolo[4,3-a]pyridine


Mass: 379.815 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H15ClFN3O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 312 / 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: 2.34 Å3/Da / Density % sol: 47.43 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.3
Details: 200 mM potassium formate, pH 7.3, 22% (W/V) PEG3350, 1.5 mM Zwittergent 3-12, vapor diffusion, hanging drop, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E / Wavelength: 1.54 / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 92 / Detector: CCD / Date: Oct 10, 2006 / Details: MICROMAX CONFOCAL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.35→50 Å / Num. obs: 49066 / % possible obs: 98.4 % / Observed criterion σ(I): 0 / Redundancy: 6.1 % / Biso Wilson estimate: 34.74 Å2 / Rmerge(I) obs: 0.038 / Net I/σ(I): 41.2
Reflection shellResolution: 2.35→2.43 Å / Redundancy: 4.3 % / Rmerge(I) obs: 0.096 / Mean I/σ(I) obs: 13 / % possible all: 87.7

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Processing

Software
NameVersionClassificationNB
BUSTER-TNTBUSTER 2.11.2refinement
PDB_EXTRACT3.11data extraction
HKL-2000(DENZO)data reduction
HKL-2000(SCALEPACK)data scaling
AMoREphasing
BUSTER2.11.2refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1XU7

1xu7


Resolution: 2.35→35.98 Å / Cor.coef. Fo:Fc: 0.9278 / Cor.coef. Fo:Fc free: 0.9109 / Occupancy max: 1 / Occupancy min: 0.5 / SU R Cruickshank DPI: 0.363 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.377 / SU Rfree Blow DPI: 0.213 / SU Rfree Cruickshank DPI: 0.214
RfactorNum. reflection% reflectionSelection details
Rfree0.2131 1046 2.14 %RANDOM
Rwork0.1886 ---
obs0.1891 48986 98.39 %-
Displacement parametersBiso mean: 27.99 Å2
Baniso -1Baniso -2Baniso -3
1-3.354 Å20 Å20 Å2
2---2.0343 Å20 Å2
3----1.3197 Å2
Refine analyzeLuzzati coordinate error obs: 0.265 Å
Refinement stepCycle: LAST / Resolution: 2.35→35.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8292 0 300 312 8904
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0098777HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1311898HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3155SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes162HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1358HARMONIC5
X-RAY DIFFRACTIONt_it8777HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.04
X-RAY DIFFRACTIONt_other_torsion18.05
X-RAY DIFFRACTIONt_improper_torsion4HARMONIC0
X-RAY DIFFRACTIONt_chiral_improper_torsion1164SEMIHARMONIC5
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_contact10587SEMIHARMONIC4
LS refinement shellResolution: 2.35→2.41 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2736 68 2.19 %
Rwork0.1992 3034 -
all0.2008 3102 -
obs--98.39 %

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