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- PDB-5hcv: Identification of Spirooxindole and Dibenzoxazepine Motifs as Pot... -

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Basic information

Entry
Database: PDB / ID: 5hcv
TitleIdentification of Spirooxindole and Dibenzoxazepine Motifs as Potent Mineralocorticoid Receptor Antagonists
ComponentsMineralocorticoid receptor
KeywordsSIGNALING PROTEIN / Mineralocorticoid Receptor / Ligand-binding domain / MR-LBD / Antagonists / co-crystal
Function / homology
Function and homology information


nuclear steroid receptor activity / estrogen response element binding / intracellular steroid hormone receptor signaling pathway / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / TBP-class protein binding / steroid binding / SUMOylation of intracellular receptors / Nuclear Receptor transcription pathway / positive regulation of non-canonical NF-kappaB signal transduction / nuclear receptor activity ...nuclear steroid receptor activity / estrogen response element binding / intracellular steroid hormone receptor signaling pathway / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / TBP-class protein binding / steroid binding / SUMOylation of intracellular receptors / Nuclear Receptor transcription pathway / positive regulation of non-canonical NF-kappaB signal transduction / nuclear receptor activity / sequence-specific double-stranded DNA binding / receptor complex / DNA-binding transcription factor activity, RNA polymerase II-specific / DNA-binding transcription factor activity / chromatin / endoplasmic reticulum membrane / regulation of transcription by RNA polymerase II / signal transduction / zinc ion binding / nucleoplasm / cytosol
Similarity search - Function
Retinoid X Receptor / Retinoid X Receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type / Zinc finger, C4 type (two domains) / Nuclear hormone receptors DNA-binding domain profile. / c4 zinc finger in nuclear hormone receptors / Nuclear hormone receptor, ligand-binding domain / Nuclear hormone receptor-like domain superfamily / Ligand-binding domain of nuclear hormone receptor ...Retinoid X Receptor / Retinoid X Receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type / Zinc finger, C4 type (two domains) / Nuclear hormone receptors DNA-binding domain profile. / c4 zinc finger in nuclear hormone receptors / Nuclear hormone receptor, ligand-binding domain / Nuclear hormone receptor-like domain superfamily / Ligand-binding domain of nuclear hormone receptor / Nuclear receptor (NR) ligand-binding (LBD) domain profile. / Ligand binding domain of hormone receptors / Zinc finger, NHR/GATA-type / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-60R / Mineralocorticoid receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsChen, G. / McKeever, B.M.
CitationJournal: Bioorg.Med.Chem. / Year: 2016
Title: Identification of spirooxindole and dibenzoxazepine motifs as potent mineralocorticoid receptor antagonists.
Authors: Lotesta, S.D. / Marcus, A.P. / Zheng, Y. / Leftheris, K. / Noto, P.B. / Meng, S. / Kandpal, G. / Chen, G. / Zhou, J. / McKeever, B. / Bukhtiyarov, Y. / Zhao, Y. / Lala, D.S. / Singh, S.B. / McGeehan, G.M.
History
DepositionJan 4, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 9, 2016Provider: repository / Type: Initial release
Revision 1.1Aug 9, 2017Group: Derived calculations / Category: pdbx_struct_oper_list / Item: _pdbx_struct_oper_list.symmetry_operation
Revision 1.2Sep 27, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
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.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Mineralocorticoid receptor
B: Mineralocorticoid receptor
C: Mineralocorticoid receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)90,7767
Polymers89,6213
Non-polymers1,1564
Water4,684260
1
A: Mineralocorticoid receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,2472
Polymers29,8741
Non-polymers3731
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Mineralocorticoid receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,2823
Polymers29,8741
Non-polymers4092
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Mineralocorticoid receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,2472
Polymers29,8741
Non-polymers3731
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)121.501, 121.501, 44.406
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number144
Space group name H-MP31
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13B
23C

NCS domain segments:

Component-ID: 0 / Beg auth comp-ID: PRO / Beg label comp-ID: PRO / End auth comp-ID: HIS / End label comp-ID: HIS / Refine code: 0 / Auth seq-ID: 738 - 982 / Label seq-ID: 11 - 255

Dom-IDEns-IDAuth asym-IDLabel asym-ID
11AA
21BB
12AA
22CC
13BB
23CC

NCS ensembles :
ID
1
2
3

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Components

#1: Protein Mineralocorticoid receptor / / MR / Nuclear receptor subfamily 3 group C member 2


Mass: 29873.594 Da / Num. of mol.: 3 / Fragment: ligand-binding domain (UNP residues 732-984) / Mutation: C808S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR3C2, MCR, MLR / Plasmid: pMAL_c5x / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (DE3) / References: UniProt: P08235
#2: Chemical ChemComp-60R / 6-[(~{E})-(3-fluoranyl-6~{H}-benzo[c][1]benzoxepin-11-ylidene)methyl]-4~{H}-1,4-benzoxazin-3-one


Mass: 373.376 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C23H16FNO3
#3: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 260 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.22 Å3/Da / Density % sol: 44.53 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 1uL of protein complex at 8-10mg protein/ml is mixed with an equal volume of reservoir solution composed of 100mM Tris-HCl pH=8.0, 200mM NaCl, 5% (v/v) glycerol, 16%(w/v) PEG3350
PH range: 7.5 - 8.5

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: CryoJet 7000
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1.075 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 28, 2011
Details: Cryogenically-cooled monochromator+vertical focusing mirror
RadiationMonochromator: sagittally-focused monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.075 Å / Relative weight: 1
ReflectionResolution: 2.5→44.41 Å / Num. all: 25409 / Num. obs: 24098 / % possible obs: 99.97 % / Observed criterion σ(I): 1 / Redundancy: 10.9 % / Rmerge(I) obs: 0.165 / Net I/σ(I): 18.5
Reflection shellResolution: 2.499→2.564 Å / Redundancy: 8.3 % / Rmerge(I) obs: 0.95 / Mean I/σ(I) obs: 2.6 / % possible all: 99.79

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Processing

Software
NameVersionClassification
REFMAC5.8.0071refinement
HKL-2000701c3.db027data reduction
SCALEPACKdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2A3I

2a3i


Resolution: 2.5→44.41 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.895 / SU B: 11.238 / SU ML: 0.249 / Cross valid method: THROUGHOUT / ESU R Free: 0.327 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.25571 1292 5.1 %RANDOM
Rwork0.16998 ---
obs0.17427 24098 99.97 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 50.713 Å2
Baniso -1Baniso -2Baniso -3
1--0.02 Å2-0.01 Å20 Å2
2---0.02 Å20 Å2
3---0.05 Å2
Refinement stepCycle: LAST / Resolution: 2.5→44.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5744 0 85 260 6089
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0195977
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.6091.988078
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5835687
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.88724.576271
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.092151084
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.6461521
X-RAY DIFFRACTIONr_chiral_restr0.1050.2883
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0214420
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.494.8222778
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it5.1677.2193455
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it4.8655.1463199
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined10.36245.83725959
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A3020.16
12B3020.16
21A2920.17
22C2920.17
31B2970.16
32C2970.16
LS refinement shellResolution: 2.499→2.564 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.316 87 -
Rwork0.218 1777 -
obs--99.79 %

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