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- PDB-5pgy: CRYSTAL STRUCTURE OF 11BETA-HSD1 DOUBLE MUTANT (L262R, F278E) COM... -

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Basic information

Entry
Database: PDB / ID: 5pgy
TitleCRYSTAL STRUCTURE OF 11BETA-HSD1 DOUBLE MUTANT (L262R, F278E) COMPLEXED WITH 2-[(5R,7S)-6-HYDROXY-2-PHENYLADAMANTAN-2-YL]-1-(3-HYDROXYAZETIDIN-1-YL)ETHAN-1-ONE (BMS-816336)
ComponentsCorticosteroid 11-beta-dehydrogenase isozyme 1
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / 11B-HSD1 / SDR / DEHYDROGENASE / HYDROXYSTEROID / INHIBITOR / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBI complex / 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-8KG / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 11-beta-hydroxysteroid dehydrogenase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.07 Å
AuthorsSheriff, S.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Discovery of Clinical Candidate 2-((2S,6S)-2-Phenyl-6-hydroxyadamantan-2-yl)-1-(3'-hydroxyazetidin-1-yl)ethanone [BMS-816336], an Orally Active Novel Selective 11 beta-Hydroxysteroid ...Title: Discovery of Clinical Candidate 2-((2S,6S)-2-Phenyl-6-hydroxyadamantan-2-yl)-1-(3'-hydroxyazetidin-1-yl)ethanone [BMS-816336], an Orally Active Novel Selective 11 beta-Hydroxysteroid Dehydrogenase Type 1 Inhibitor.
Authors: Ye, X.Y. / Chen, S.Y. / Wu, S. / Yoon, D.S. / Wang, H. / Hong, Z. / O'Connor, S.P. / Li, J. / Li, J.J. / Kennedy, L.J. / Walker, S.J. / Nayeem, A. / Sheriff, S. / Camac, D.M. / Ramamurthy, V. ...Authors: Ye, X.Y. / Chen, S.Y. / Wu, S. / Yoon, D.S. / Wang, H. / Hong, Z. / O'Connor, S.P. / Li, J. / Li, J.J. / Kennedy, L.J. / Walker, S.J. / Nayeem, A. / Sheriff, S. / Camac, D.M. / Ramamurthy, V. / Morin, P.E. / Zebo, R. / Taylor, J.R. / Morgan, N.N. / Ponticiello, R.P. / Harrity, T. / Apedo, A. / Golla, R. / Seethala, R. / Wang, M. / Harper, T.W. / Sleczka, B.G. / He, B. / Kirby, M. / Leahy, D.K. / Li, J. / Hanson, R.L. / Guo, Z. / Li, Y.X. / DiMarco, J.D. / Scaringe, R. / Maxwell, B. / Moulin, F. / Barrish, J.C. / Gordon, D.A. / Robl, J.A.
History
DepositionFeb 6, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 1, 2017Provider: repository / Type: Initial release
Revision 1.1Feb 21, 2018Group: Structure summary / Category: pdbx_deposit_group / Item: _pdbx_deposit_group.group_type
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)129,72512
Polymers125,3854
Non-polymers4,3398
Water4,558253
1
A: Corticosteroid 11-beta-dehydrogenase isozyme 1
B: Corticosteroid 11-beta-dehydrogenase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,8626
Polymers62,6932
Non-polymers2,1704
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7900 Å2
ΔGint-58 kcal/mol
Surface area21760 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)64,8626
Polymers62,6932
Non-polymers2,1704
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7830 Å2
ΔGint-59 kcal/mol
Surface area21560 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.500, 92.300, 162.400
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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-beta-HSD1 / Short chain dehydrogenase/reductase family ...11-beta-hydroxysteroid dehydrogenase 1 / 11-beta-HSD1 / Short chain dehydrogenase/reductase family 26C member 1


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, SDR26C1 / 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-8KG / 2-[(5R,7S)-6-HYDROXY-2-PHENYLADAMANTAN-2-YL]-1-(3-HYDROXYAZETIDIN-1-YL)ETHAN-1-ONE


Mass: 341.444 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H27NO3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 253 / 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: 2.23 Å3/Da / Density % sol: 44.76 %
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

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-BM / Wavelength: 1 / Wavelength: 1 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Oct 18, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.07→50 Å / Num. obs: 54263 / % possible obs: 78.4 % / Observed criterion σ(I): 0 / Redundancy: 4.9 % / Biso Wilson estimate: 28.71 Å2 / Rsym value: 0.049 / Net I/σ(I): 27.2
Reflection shellResolution: 2.07→2.14 Å / Redundancy: 2.5 % / Mean I/σ(I) obs: 4.1 / Rsym value: 0.25 / Rejects: 0 / % possible all: 48.5

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
HKL-2000data collection
HKL-2000data scaling
AMoREphasing
BUSTER2.11.7refinement
PDB_EXTRACT3.22data extraction
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4IJU

4iju


Resolution: 2.07→28.54 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.908 / SU R Cruickshank DPI: 0.286 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.283 / SU Rfree Blow DPI: 0.201 / SU Rfree Cruickshank DPI: 0.203
RfactorNum. reflection% reflectionSelection details
Rfree0.226 1114 2.05 %RANDOM
Rwork0.186 ---
obs0.187 54218 78.6 %-
Displacement parametersBiso max: 154.29 Å2 / Biso mean: 33.11 Å2 / Biso min: 5.22 Å2
Baniso -1Baniso -2Baniso -3
1-5.0308 Å20 Å20 Å2
2---3.4792 Å20 Å2
3----1.5517 Å2
Refine analyzeLuzzati coordinate error obs: 0.27 Å
Refinement stepCycle: final / Resolution: 2.07→28.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8193 0 292 253 8738
Biso mean--24.62 28.43 -
Num. residues----1079
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3146SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes160HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1428HARMONIC5
X-RAY DIFFRACTIONt_it8868HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1153SEMIHARMONIC5
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_contact10791SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d8868HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg12223HARMONIC21.04
X-RAY DIFFRACTIONt_omega_torsion3.16
X-RAY DIFFRACTIONt_other_torsion16.56
LS refinement shellResolution: 2.07→2.12 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2845 54 2.45 %
Rwork0.2177 2148 -
all0.2193 2202 -
obs--43.96 %

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