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- PDB-2irw: Human 11-beta-Hydroxysteroid Dehydrogenase (HSD1) with NADP and A... -

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Basic information

Entry
Database: PDB / ID: 2irw
TitleHuman 11-beta-Hydroxysteroid Dehydrogenase (HSD1) with NADP and Adamantane Ether Inhibitor
ComponentsCorticosteroid 11-beta-dehydrogenase isozyme 1
KeywordsOXIDOREDUCTASE / HSD1 / NADP / inhibitor
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
NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Chem-NN4 / 11-beta-hydroxysteroid dehydrogenase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.1 Å
AuthorsLongenecker, K.L. / Patel, J.R. / Russell, J. / Qin, W.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2007
Title: Discovery of adamantane ethers as inhibitors of 11beta-HSD-1: Synthesis and biological evaluation.
Authors: Patel, J.R. / Shuai, Q. / Dinges, J. / Winn, M. / Pliushchev, M. / Fung, S. / Monzon, K. / Chiou, W. / Wang, J. / Pan, L. / Wagaw, S. / Engstrom, K. / Kerdesky, F.A. / Longenecker, K. / ...Authors: Patel, J.R. / Shuai, Q. / Dinges, J. / Winn, M. / Pliushchev, M. / Fung, S. / Monzon, K. / Chiou, W. / Wang, J. / Pan, L. / Wagaw, S. / Engstrom, K. / Kerdesky, F.A. / Longenecker, K. / Judge, R. / Qin, W. / Imade, H.M. / Stolarik, D. / Beno, D.W. / Brune, M. / Chovan, L.E. / Sham, H.L. / Jacobson, P. / Link, J.T.
History
DepositionOct 16, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 23, 2007Provider: repository / Type: Initial release
Revision 1.1Oct 24, 2007Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Derived calculations / Version format compliance
Revision 1.3Oct 18, 2017Group: Refinement description / Category: software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.date / _software.language / _software.location / _software.name / _software.type / _software.version
Revision 1.4Jan 24, 2018Group: Structure summary / Category: audit_author / Item: _audit_author.name
Revision 1.5Feb 21, 2024Group: 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 / struct_ncs_dom_lim / 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_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.end_auth_comp_id / _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
E: Corticosteroid 11-beta-dehydrogenase isozyme 1
F: Corticosteroid 11-beta-dehydrogenase isozyme 1
G: Corticosteroid 11-beta-dehydrogenase isozyme 1
H: Corticosteroid 11-beta-dehydrogenase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)241,36624
Polymers232,3268
Non-polymers9,03916
Water0
1
A: Corticosteroid 11-beta-dehydrogenase isozyme 1
B: Corticosteroid 11-beta-dehydrogenase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,3416
Polymers58,0822
Non-polymers2,2604
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10260 Å2
ΔGint-61 kcal/mol
Surface area20240 Å2
MethodPISA, PQS
2
C: Corticosteroid 11-beta-dehydrogenase isozyme 1
D: Corticosteroid 11-beta-dehydrogenase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,3416
Polymers58,0822
Non-polymers2,2604
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9590 Å2
ΔGint-57 kcal/mol
Surface area20070 Å2
MethodPISA, PQS
3
E: Corticosteroid 11-beta-dehydrogenase isozyme 1
F: Corticosteroid 11-beta-dehydrogenase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,3416
Polymers58,0822
Non-polymers2,2604
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9650 Å2
ΔGint-56 kcal/mol
Surface area20080 Å2
MethodPISA, PQS
4
G: Corticosteroid 11-beta-dehydrogenase isozyme 1
H: Corticosteroid 11-beta-dehydrogenase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,3416
Polymers58,0822
Non-polymers2,2604
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10290 Å2
ΔGint-65 kcal/mol
Surface area20310 Å2
MethodPISA, PQS
Unit cell
Length a, b, c (Å)184.537, 184.537, 558.052
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number155
Space group name H-MH32
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12C
22D
13E
23F
14G
24H

NCS domain segments:

Component-ID: 1 / Beg auth comp-ID: GLU / Beg label comp-ID: GLU

Dom-IDEns-IDEnd auth comp-IDEnd label comp-IDRefine codeAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11PHEPHE1AA26 - 2891 - 264
21PHEPHE1BB26 - 2891 - 264
12THRTHR1CC26 - 2821 - 257
22PHEPHE1DD26 - 2891 - 264
13THRTHR4EE26 - 2821 - 257
23PHEPHE4FF26 - 2891 - 264
14PHEPHE4GG26 - 2891 - 264
24PHEPHE4HH26 - 2891 - 264

NCS ensembles :
ID
1
2
3
4

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Components

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


Mass: 29040.803 Da / Num. of mol.: 8 / Fragment: dehydrogenase domain (residues 25-288)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSD11B1
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.: 8 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#3: Chemical
ChemComp-NN4 / (1S,3R,4S,5S,7S)-4-{[2-(4-METHOXYPHENOXY)-2-METHYLPROPANOYL]AMINO}ADAMANTANE-1-CARBOXAMIDE


Mass: 386.485 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C22H30N2O4

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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: 3.93 Å3/Da / Density % sol: 68.74 %
Crystal growMethod: vapor diffusion / Details: VAPOR DIFFUSION

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.1→182.57 Å / Num. obs: 66694 / % possible obs: 100 % / Redundancy: 5.6 % / Rmerge(I) obs: 0.113 / Χ2: 1.203 / Net I/σ(I): 7.2
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
3.1-3.215.50.47765901.1881100
3.21-3.345.50.3566071.221100
3.34-3.495.60.25765991.2171100
3.49-3.685.60.17866171.2341100
3.68-3.915.60.13666151.2271100
3.91-4.215.70.10466581.1951100
4.21-4.635.70.07766461.2141100
4.63-5.35.60.0766791.1521100
5.3-6.675.60.07867471.1431100
6.67-505.30.04169361.24199.9

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMAC5.2.0019refinement
PDB_EXTRACT2data extraction
HKL-2000data collection
HKL-2000data reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.1→182.57 Å / Cor.coef. Fo:Fc: 0.924 / Cor.coef. Fo:Fc free: 0.883 / SU B: 19.102 / SU ML: 0.342 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.45 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. THERE ARE LARGE BOND DEVIATIONS FOR LYS 238 IN ALL CHAINS.
RfactorNum. reflection% reflectionSelection details
Rfree0.278 3377 5.1 %RANDOM
Rwork0.237 ---
obs0.239 66684 99.93 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 41.637 Å2
Baniso -1Baniso -2Baniso -3
1-2.24 Å21.12 Å20 Å2
2--2.24 Å20 Å2
3----3.36 Å2
Refinement stepCycle: LAST / Resolution: 3.1→182.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms16120 0 608 0 16728
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.02217060
X-RAY DIFFRACTIONr_angle_refined_deg1.2472.00723152
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.43352090
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.25823.698622
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.165152978
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.4811578
X-RAY DIFFRACTIONr_chiral_restr0.0770.22690
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0212240
X-RAY DIFFRACTIONr_nbd_refined0.2050.28071
X-RAY DIFFRACTIONr_nbtor_refined0.3050.211861
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.130.2496
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2620.253
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0610.24
X-RAY DIFFRACTIONr_mcbond_it0.3441.510630
X-RAY DIFFRACTIONr_mcangle_it0.63216696
X-RAY DIFFRACTIONr_scbond_it0.86437216
X-RAY DIFFRACTIONr_scangle_it1.5154.56456
Refine LS restraints NCS

Dom-ID: 1 / Refine-ID: X-RAY DIFFRACTION

Ens-IDAuth asym-IDNumberTypeRms dev position (Å)Weight position
1A2107TIGHT POSITIONAL0.030.05
1A2107TIGHT THERMAL0.140.5
2C2043TIGHT POSITIONAL0.040.05
2C2043TIGHT THERMAL0.060.5
3E2043MEDIUM POSITIONAL0.210.5
3E2043MEDIUM THERMAL0.52
4G2107MEDIUM POSITIONAL0.160.5
4G2107MEDIUM THERMAL0.682
LS refinement shellResolution: 3.1→3.181 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.361 247 -
Rwork0.314 4633 -
obs-4880 99.9 %

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