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- PDB-8a9g: Binary complex of 14-3-3 zeta Glucocorticoid Receptor (GR) pT524 ... -

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Basic information

Entry
Database: PDB / ID: 8a9g
TitleBinary complex of 14-3-3 zeta Glucocorticoid Receptor (GR) pT524 peptide stabilised by (R)-para chloropyrrolidone1
Components
  • 14-3-3 protein zeta/delta
  • Glucocorticoid receptor
KeywordsPROTEIN BINDING / 14-3-3 protein zeta/delta / Glucocorticoid Receptor / (R)-para chloropyrrolidone1 / protein-peptide complex / protein-protein interaction / PPI stabilisation / molecular glue / pyrrolidone1 analogue
Function / homology
Function and homology information


Regulation of NPAS4 gene transcription / synaptic target recognition / regulation of glucocorticoid biosynthetic process / Golgi reassembly / nuclear glucocorticoid receptor activity / steroid hormone binding / PTK6 Expression / NOTCH4 Activation and Transmission of Signal to the Nucleus / glucocorticoid metabolic process / establishment of Golgi localization ...Regulation of NPAS4 gene transcription / synaptic target recognition / regulation of glucocorticoid biosynthetic process / Golgi reassembly / nuclear glucocorticoid receptor activity / steroid hormone binding / PTK6 Expression / NOTCH4 Activation and Transmission of Signal to the Nucleus / glucocorticoid metabolic process / establishment of Golgi localization / neuroinflammatory response / mammary gland duct morphogenesis / respiratory system process / microglia differentiation / regulation of synapse maturation / tube formation / astrocyte differentiation / Rap1 signalling / maternal behavior / negative regulation of protein localization to nucleus / cellular response to glucocorticoid stimulus / motor behavior / KSRP (KHSRP) binds and destabilizes mRNA / adrenal gland development / regulation of gluconeogenesis / GP1b-IX-V activation signalling / cellular response to steroid hormone stimulus / Regulation of localization of FOXO transcription factors / Interleukin-3, Interleukin-5 and GM-CSF signaling / phosphoserine residue binding / Activation of BAD and translocation to mitochondria / estrogen response element binding / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / protein targeting / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / nuclear receptor-mediated steroid hormone signaling pathway / regulation of ERK1 and ERK2 cascade / core promoter sequence-specific DNA binding / cellular response to glucose starvation / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / RHO GTPases activate PKNs / cellular response to transforming growth factor beta stimulus / negative regulation of TORC1 signaling / steroid binding / TBP-class protein binding / protein sequestering activity / ERK1 and ERK2 cascade / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / cellular response to dexamethasone stimulus / negative regulation of innate immune response / hippocampal mossy fiber to CA3 synapse / synaptic transmission, glutamatergic / Translocation of SLC2A4 (GLUT4) to the plasma membrane / RNA polymerase II transcription regulatory region sequence-specific DNA binding / TP53 Regulates Metabolic Genes / chromosome segregation / Deactivation of the beta-catenin transactivating complex / lung development / SUMOylation of intracellular receptors / Hsp90 protein binding / Negative regulation of NOTCH4 signaling / regulation of protein stability / positive regulation of miRNA transcription / Nuclear Receptor transcription pathway / spindle / DNA-binding transcription repressor activity, RNA polymerase II-specific / nuclear receptor activity / Regulation of RUNX2 expression and activity / sequence-specific double-stranded DNA binding / positive regulation of neuron apoptotic process / : / protein localization / melanosome / chromatin organization / DNA-binding transcription activator activity, RNA polymerase II-specific / angiogenesis / gene expression / DNA-binding transcription factor binding / blood microparticle / vesicle / transmembrane transporter binding / Potential therapeutics for SARS / DNA-binding transcription factor activity, RNA polymerase II-specific / nuclear speck / mitochondrial matrix / cadherin binding / protein phosphorylation / protein domain specific binding / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / cell division / focal adhesion / negative regulation of DNA-templated transcription / centrosome / apoptotic process / ubiquitin protein ligase binding / synapse / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II
Similarity search - Function
Glucocorticoid receptor / Glucocorticoid receptor / 14-3-3 domain / Delta-Endotoxin; domain 1 / 14-3-3 proteins signature 2. / 14-3-3 protein, conserved site / 14-3-3 proteins signature 1. / 14-3-3 protein / 14-3-3 homologues / 14-3-3 domain ...Glucocorticoid receptor / Glucocorticoid receptor / 14-3-3 domain / Delta-Endotoxin; domain 1 / 14-3-3 proteins signature 2. / 14-3-3 protein, conserved site / 14-3-3 proteins signature 1. / 14-3-3 protein / 14-3-3 homologues / 14-3-3 domain / 14-3-3 domain superfamily / 14-3-3 protein / : / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type / Double treble clef zinc finger, C4 type / 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 / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-QJK / Glucocorticoid receptor / 14-3-3 protein zeta/delta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.961 Å
AuthorsMunier, C.C. / Edman, K. / Perry, M.W.D. / Ottmann, C.
Funding supportEuropean Union, 1items
OrganizationGrant numberCountry
European Commission675179European Union
CitationJournal: J.Med.Chem. / Year: 2022
Title: Designing Selective Drug-like Molecular Glues for the Glucocorticoid Receptor/14-3-3 Protein-Protein Interaction.
Authors: Pallesen, J.S. / Munier, C.C. / Bosica, F. / Andrei, S.A. / Edman, K. / Gunnarsson, A. / La Sala, G. / Putra, O.D. / Srdanovic, S. / Wilson, A.J. / Wissler, L. / Ottmann, C. / Perry, M.W.D. / O'Mahony, G.
History
DepositionJun 28, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 28, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 4, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 14-3-3 protein zeta/delta
B: 14-3-3 protein zeta/delta
C: Glucocorticoid receptor
D: Glucocorticoid receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,7929
Polymers56,3604
Non-polymers1,4325
Water5,098283
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5790 Å2
ΔGint-29 kcal/mol
Surface area23090 Å2
Unit cell
Length a, b, c (Å)57.350, 78.070, 122.570
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP22121

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Components

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Protein / Protein/peptide , 2 types, 4 molecules ABCD

#1: Protein 14-3-3 protein zeta/delta / Protein kinase C inhibitor protein 1 / KCIP-1


Mass: 26720.217 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: YWHAZ / Plasmid: pProEx Htb / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): STAR / References: UniProt: P63104
#2: Protein/peptide Glucocorticoid receptor / GR / Nuclear receptor subfamily 3 group C member 1


Mass: 1459.642 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P04150

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Non-polymers , 4 types, 288 molecules

#3: Chemical ChemComp-BTB / 2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / BIS-TRIS BUFFER


Mass: 209.240 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H19NO5 / Comment: pH buffer*YM
#4: Chemical ChemComp-QJK / 5-[(2~{R})-3-(4-chlorophenyl)carbonyl-2-(4-nitrophenyl)-4-oxidanyl-5-oxidanylidene-2~{H}-pyrrol-1-yl]-2-oxidanyl-benzoic acid


Mass: 494.838 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H15ClN2O8 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 283 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.43 Å3/Da / Density % sol: 49.47 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: 0.4 M MgCl2 27% w/v PEG 3350 0.1 M Bis Tris 6.5 pH

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1.00003 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 5, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00003 Å / Relative weight: 1
ReflectionResolution: 1.961→65.85 Å / Num. obs: 31964 / % possible obs: 94.1 % / Redundancy: 7.4 % / Biso Wilson estimate: 40.63 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.089 / Rpim(I) all: 0.035 / Rrim(I) all: 0.095 / Net I/σ(I): 12.7
Reflection shellResolution: 1.961→2.133 Å / Redundancy: 6.9 % / Rmerge(I) obs: 1.381 / Mean I/σ(I) obs: 1.5 / Num. unique obs: 1599 / CC1/2: 0.592 / Rpim(I) all: 0.562 / % possible all: 55.3

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
PHASERphasing
BUSTER2.11.8 (24-FEB-2021)refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2O02

2o02


Resolution: 1.961→65.85 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.934 / SU R Cruickshank DPI: 0.283 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.301 / SU Rfree Blow DPI: 0.205 / SU Rfree Cruickshank DPI: 0.202
RfactorNum. reflection% reflectionSelection details
Rfree0.2612 1587 4.96 %RANDOM
Rwork0.25 ---
obs0.2506 31964 78.7 %-
Displacement parametersBiso max: 130.2 Å2 / Biso mean: 45.4 Å2 / Biso min: 8.54 Å2
Baniso -1Baniso -2Baniso -3
1-1.3373 Å20 Å20 Å2
2--0.4521 Å20 Å2
3----1.7894 Å2
Refine analyzeLuzzati coordinate error obs: 0.34 Å
Refinement stepCycle: final / Resolution: 1.961→65.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3879 0 99 283 4261
Biso mean--84.24 48.03 -
Num. residues----485
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1477SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes690HARMONIC5
X-RAY DIFFRACTIONt_it4044HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion520SEMIHARMONIC5
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_contact4340SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4044HARMONIC20.026
X-RAY DIFFRACTIONt_angle_deg5461HARMONIC21.37
X-RAY DIFFRACTIONt_omega_torsion2.27
X-RAY DIFFRACTIONt_other_torsion22.55
LS refinement shellResolution: 1.961→2.08 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.3987 40 6.25 %
Rwork0.3307 600 -
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.96640.59780.37920.56210.44920.89820.00970.1346-0.19730.1027-0.0970.06080.5554-0.30460.0873-0.0351-0.22950.0764-0.3103-0.1111-0.30226.199619.200219.1322
21.43330.0696-0.2870.36930.86491.84610.02040.05720.06070.00220.08140.0020.0492-0.1078-0.1019-0.44210.03430.0136-0.47310.0667-0.469235.077856.924978.3639
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A1 - 230
2X-RAY DIFFRACTION2{ B|* }B1 - 230

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