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

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Basic information

Entry
Database: PDB / ID: 5qii
TitleCRYSTAL STRUCTURE OF 11BETA-HSD1 DOUBLE MUTANT (L262R, F278E) COMPLEXED WITH 2-(3-(1-(4-CHLOROPHENYL)CYCLOPROPYL) -[1,2,4]TRIAZOLO[4,3-A]PYRIDIN-8-YL)PROPAN-2-OL
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-HJG / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 11-beta-hydroxysteroid dehydrogenase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.45 Å
AuthorsSheriff, S.
CitationJournal: ACS Med Chem Lett / Year: 2018
Title: Discovery of Clinical Candidate BMS-823778 as an Inhibitor of Human 11 beta-Hydroxysteroid Dehydrogenase Type 1 (11 beta-HSD-1).
Authors: Li, J. / Kennedy, L.J. / Walker, S.J. / Wang, H. / Li, J.J. / Hong, Z. / O'Connor, S.P. / Ye, X.Y. / Chen, S. / Wu, S. / Yoon, D.S. / Nayeem, A. / Camac, D.M. / Ramamurthy, V. / Morin, P.E. ...Authors: Li, J. / Kennedy, L.J. / Walker, S.J. / Wang, H. / Li, J.J. / Hong, Z. / O'Connor, S.P. / Ye, X.Y. / Chen, S. / Wu, S. / Yoon, D.S. / Nayeem, A. / Camac, D.M. / Ramamurthy, V. / Morin, P.E. / Sheriff, S. / Wang, M. / Harper, T.W. / Golla, R. / Seethala, R. / Harrity, T. / Ponticiello, R.P. / Morgan, N.N. / Taylor, J.R. / Zebo, R. / Maxwell, B. / Moulin, F. / Gordon, D.A. / Robl, J.A.
History
DepositionJul 3, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 19, 2018Provider: repository / Type: Initial release
Revision 1.1Jan 16, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_volume ..._citation.journal_abbrev / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2May 12, 2021Group: Structure summary / Category: pdbx_deposit_group / Item: _pdbx_deposit_group.group_type
Revision 1.3Mar 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)129,67012
Polymers125,3854
Non-polymers4,2858
Water2,288127
1
A: Corticosteroid 11-beta-dehydrogenase isozyme 1
B: Corticosteroid 11-beta-dehydrogenase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,8356
Polymers62,6932
Non-polymers2,1424
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8030 Å2
ΔGint-60 kcal/mol
Surface area20170 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)64,8356
Polymers62,6932
Non-polymers2,1424
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7920 Å2
ΔGint-58 kcal/mol
Surface area21200 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.500, 93.900, 162.700
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 BL21(DE3) (bacteria) / 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-HJG / 2-{3-[1-(4-chlorophenyl)cyclopropyl][1,2,4]triazolo[4,3-a]pyridin-8-yl}propan-2-ol


Mass: 327.808 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H18ClN3O
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 127 / 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: 2.27 Å3/Da / Density % sol: 45.8 %
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: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.54 / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 92 / Detector: CCD / Date: Sep 23, 2007 / Details: MICROMAX CONFOCAL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.45→50 Å / Num. obs: 42305 / % possible obs: 98.7 % / Observed criterion σ(I): 0 / Redundancy: 5.1 % / Biso Wilson estimate: 44.39 Å2 / Rmerge(I) obs: 0.138 / Net I/σ(I): 10.9
Reflection shellResolution: 2.45→2.54 Å / Redundancy: 4.6 % / Rmerge(I) obs: 0.509 / Mean I/σ(I) obs: 3.3 / Rejects: 0 / % possible all: 99.2

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
HKL-2000data reduction
HKL-2000data scaling
AMoREphasing
BUSTER2.11.7refinement
PDB_EXTRACT3.22data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3TFQ

3tfq


Resolution: 2.45→46.96 Å / Cor.coef. Fo:Fc: 0.884 / Cor.coef. Fo:Fc free: 0.839 / SU R Cruickshank DPI: 0.59 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.564 / SU Rfree Blow DPI: 0.284 / SU Rfree Cruickshank DPI: 0.288
RfactorNum. reflection% reflectionSelection details
Rfree0.261 1071 2.54 %RANDOM
Rwork0.222 ---
obs0.223 42172 98.7 %-
Displacement parametersBiso max: 122.74 Å2 / Biso mean: 35.42 Å2 / Biso min: 3 Å2
Baniso -1Baniso -2Baniso -3
1-4.7713 Å20 Å20 Å2
2--1.0499 Å20 Å2
3----5.8211 Å2
Refine analyzeLuzzati coordinate error obs: 0.38 Å
Refinement stepCycle: final / Resolution: 2.45→46.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8126 0 284 127 8537
Biso mean--25.98 19.37 -
Num. residues----1065
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3071SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1638HARMONIC5
X-RAY DIFFRACTIONt_it8763HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1143SEMIHARMONIC5
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_contact10402SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d8763HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg12023HARMONIC21.09
X-RAY DIFFRACTIONt_omega_torsion2.75
X-RAY DIFFRACTIONt_other_torsion17.59
LS refinement shellResolution: 2.45→2.51 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.341 86 2.8 %
Rwork0.2687 2980 -
all0.2706 3066 -
obs--99.17 %

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