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- PDB-3tfq: Crystal structure of 11b-hsd1 double mutant (l262r, f278e) comple... -

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Basic information

Entry
Database: PDB / ID: 3tfq
TitleCrystal structure of 11b-hsd1 double mutant (l262r, f278e) complexed with 8-{[(2-CYANOPYRIDIN-3-YL)METHYL]SULFANYL}-6-HYDROXY-3,4-DIHYDRO-1H-PYRANO[3,4-C]PYRIDINE-5-CARBONITRILE
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


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-07M / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 11-beta-hydroxysteroid dehydrogenase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsSheriff, S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Discovery of 3-hydroxy-4-cyano-isoquinolines as novel, potent, and selective inhibitors of human 11beta-hydroxydehydrogenase 1 (11beta-HSD1)
Authors: Wu, S.C. / Yoon, D. / Chin, J. / van Kirk, K. / Seethala, R. / Golla, R. / He, B. / Harrity, T. / Kunselman, L.K. / Morgan, N.N. / Ponticiello, R.P. / Taylor, J.R. / Zebo, R. / Harper, T.W. ...Authors: Wu, S.C. / Yoon, D. / Chin, J. / van Kirk, K. / Seethala, R. / Golla, R. / He, B. / Harrity, T. / Kunselman, L.K. / Morgan, N.N. / Ponticiello, R.P. / Taylor, J.R. / Zebo, R. / Harper, T.W. / Li, W. / Wang, M. / Zhang, L. / Sleczka, B.G. / Nayeem, A. / Sheriff, S. / Camac, D.M. / Morin, P.E. / Everlof, J.G. / Li, Y.X. / Ferraro, C.A. / Kieltyka, K. / Shou, W. / Vath, M.B. / Zvyaga, T.A. / Gordon, D.A. / Robl, J.A.
History
DepositionAug 16, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 2, 2011Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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
Revision 1.2Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)129,74913
Polymers125,3854
Non-polymers4,3639
Water14,664814
1
A: Corticosteroid 11-beta-dehydrogenase isozyme 1
B: Corticosteroid 11-beta-dehydrogenase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,8286
Polymers62,6932
Non-polymers2,1364
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8080 Å2
ΔGint-61 kcal/mol
Surface area21890 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)64,9207
Polymers62,6932
Non-polymers2,2285
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7700 Å2
ΔGint-54 kcal/mol
Surface area21980 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.500, 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 / Nicotinamide adenine dinucleotide phosphate


Mass: 743.405 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#3: Chemical
ChemComp-07M / 8-{[(2-cyanopyridin-3-yl)methyl]sulfanyl}-6-hydroxy-3,4-dihydro-1H-pyrano[3,4-c]pyridine-5-carbonitrile


Mass: 324.357 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C16H12N4O2S
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 814 / 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: 47.5 %
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: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Oct 13, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→50 Å / Num. obs: 106364 / % possible obs: 97 % / Observed criterion σ(I): 0 / Redundancy: 4.4 % / Biso Wilson estimate: 21.54 Å2 / Rmerge(I) obs: 0.038 / Net I/σ(I): 35.1
Reflection shellResolution: 1.8→1.86 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.088 / Mean I/σ(I) obs: 14.8 / % possible all: 96.7

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Processing

Software
NameVersionClassificationNB
BUSTER-TNTBUSTER 2.11.1refinement
PDB_EXTRACT3.1data extraction
HKL-2000(DENZO)data reduction
HKL-2000(SCALEPACK)data scaling
AMoREphasing
BUSTER2.11.1refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 11BHSD/LIGAND

Resolution: 1.8→26.35 Å / Cor.coef. Fo:Fc: 0.9494 / Cor.coef. Fo:Fc free: 0.9348 / Occupancy max: 1 / Occupancy min: 0.5 / SU R Cruickshank DPI: 0.11 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.1933 2223 2.09 %RANDOM
Rwork0.1653 ---
obs0.1659 106304 96.92 %-
Displacement parametersBiso max: 111.96 Å2 / Biso mean: 23.8595 Å2 / Biso min: 4.89 Å2
Baniso -1Baniso -2Baniso -3
1-3.9346 Å20 Å20 Å2
2---1.56 Å20 Å2
3----2.3745 Å2
Refine analyzeLuzzati coordinate error obs: 0.17 Å
Refinement stepCycle: LAST / Resolution: 1.8→26.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8221 0 290 814 9325
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3116SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes193HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1258HARMONIC5
X-RAY DIFFRACTIONt_it8729HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1152SEMIHARMONIC5
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_contact10992SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d8729HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg11811HARMONIC20.99
X-RAY DIFFRACTIONt_omega_torsion3.41
X-RAY DIFFRACTIONt_other_torsion16.31
LS refinement shellResolution: 1.8→1.85 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2272 177 2.35 %
Rwork0.1794 7366 -
all0.1804 7543 -
obs--96.92 %

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