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- PDB-4k1l: 4,4-Dioxo-5,6-dihydro-[1,4,3]oxathiazines, a novel class of 11 be... -

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Basic information

Entry
Database: PDB / ID: 4k1l
Title4,4-Dioxo-5,6-dihydro-[1,4,3]oxathiazines, a novel class of 11 beta-HSD1 inhibitors for the treatment of diabetes
ComponentsCorticosteroid 11-beta-dehydrogenase isozyme 1
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / 11-beta-hydroxysteroid dehydrogenase 1 / 11-DH / 11-beta-HSD1 / short chain dehydrogenase / 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-NDP / Chem-SFF / 11-beta-hydroxysteroid dehydrogenase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.96 Å
AuthorsLoenze, P. / Schimanski-Breves, S. / Von der Heyden, C. / Engel, C.K.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: 1,1-Dioxo-5,6-dihydro-[4,1,2]oxathiazines, a novel class of 11-HSD1 inhibitors for the treatment of diabetes.
Authors: Bohme, T. / Engel, C.K. / Farjot, G. / Gussregen, S. / Haack, T. / Tschank, G. / Ritter, K.
History
DepositionApr 5, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 9, 2014Provider: repository / Type: Initial release
Revision 1.1Sep 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
C: Corticosteroid 11-beta-dehydrogenase isozyme 1
D: Corticosteroid 11-beta-dehydrogenase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)131,47512
Polymers127,3484
Non-polymers4,1278
Water11,043613
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area17420 Å2
ΔGint-140 kcal/mol
Surface area39260 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.361, 150.941, 74.169
Angle α, β, γ (deg.)90.00, 93.79, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 31836.875 Da / Num. of mol.: 4 / Mutation: C272S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSD11B1, HSD11, HSD11L / Production host: Escherichia coli (E. coli)
References: UniProt: P28845, 11beta-hydroxysteroid dehydrogenase
#2: Chemical
ChemComp-SFF / (4aS,8aR)-N-cyclohexyl-4a,5,6,7,8,8a-hexahydro-4,1,2-benzoxathiazin-3-amine 1,1-dioxide


Mass: 286.390 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C13H22N2O3S
#3: Chemical
ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE


Mass: 745.421 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 613 / 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: 2.52 Å3/Da / Density % sol: 51.11 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 40% PEG300, 0.1M MES, pH 6.5, vapor diffusion, temperature 277K, VAPOR DIFFUSION, HANGING DROP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-1
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: May 15, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 1.96→75.46 Å / Num. all: 89991 / Num. obs: 89812 / % possible obs: 99.8 % / Observed criterion σ(F): -3 / Observed criterion σ(I): -3 / Biso Wilson estimate: 22.42 Å2
Reflection shellResolution: 1.96→2.03 Å / Redundancy: 3.78 % / Rmerge(I) obs: 0.261 / Mean I/σ(I) obs: 5.18 / % possible all: 100

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Processing

Software
NameClassification
BUSTERrefinement
XDSdata reduction
XSCALEdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB ENTRY 1XU9

1xu9


Resolution: 1.96→28.62 Å / Cor.coef. Fo:Fc: 0.9504 / Cor.coef. Fo:Fc free: 0.9333 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2019 4409 4.91 %RANDOM
Rwork0.167 ---
obs0.1688 89790 99.82 %-
all-89991 --
Displacement parametersBiso mean: 24.77 Å2
Baniso -1Baniso -2Baniso -3
1-0.1648 Å20 Å2-0.0672 Å2
2---0.2983 Å20 Å2
3---0.1335 Å2
Refine analyzeLuzzati coordinate error obs: 0.19 Å
Refinement stepCycle: LAST / Resolution: 1.96→28.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8109 0 268 613 8990
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.018673HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1211766HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3119SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes169HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1306HARMONIC5
X-RAY DIFFRACTIONt_it8673HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.25
X-RAY DIFFRACTIONt_other_torsion17.26
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1109SEMIHARMONIC5
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_contact11227SEMIHARMONIC4
LS refinement shellResolution: 1.96→2.01 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2327 308 4.65 %
Rwork0.1885 6311 -
all0.1906 6619 -
obs--99.82 %

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