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- PDB-6rhc: Fragment AZ-003 binding at the TAZpS89/14-3-3 sigma interface -

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Basic information

Entry
Database: PDB / ID: 6rhc
TitleFragment AZ-003 binding at the TAZpS89/14-3-3 sigma interface
Components
  • 14-3-3 protein sigma
  • WW domain-containing transcription regulator protein 1
KeywordsPEPTIDE BINDING PROTEIN / protein protein interaction / fragment soaking / stabilization
Function / homology
Function and homology information


kidney morphogenesis / regulation of metanephric nephron tubule epithelial cell differentiation / RUNX3 regulates YAP1-mediated transcription / Physiological factors / mesenchymal cell differentiation / heart process / YAP1- and WWTR1 (TAZ)-stimulated gene expression / hippo signaling / EGR2 and SOX10-mediated initiation of Schwann cell myelination / tissue homeostasis ...kidney morphogenesis / regulation of metanephric nephron tubule epithelial cell differentiation / RUNX3 regulates YAP1-mediated transcription / Physiological factors / mesenchymal cell differentiation / heart process / YAP1- and WWTR1 (TAZ)-stimulated gene expression / hippo signaling / EGR2 and SOX10-mediated initiation of Schwann cell myelination / tissue homeostasis / SMAD protein signal transduction / glomerulus development / stem cell division / Signaling by Hippo / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / regulation of epidermal cell division / protein kinase C inhibitor activity / negative regulation of fat cell differentiation / positive regulation of epidermal cell differentiation / keratinocyte development / keratinization / RUNX2 regulates osteoblast differentiation / regulation of cell-cell adhesion / cAMP/PKA signal transduction / Regulation of localization of FOXO transcription factors / keratinocyte proliferation / cilium assembly / phosphoserine residue binding / Activation of BAD and translocation to mitochondria / negative regulation of keratinocyte proliferation / bicellular tight junction / establishment of skin barrier / negative regulation of protein localization to plasma membrane / positive regulation of osteoblast differentiation / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / positive regulation of epithelial to mesenchymal transition / negative regulation of stem cell proliferation / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / RHO GTPases activate PKNs / positive regulation of protein localization / positive regulation of cell adhesion / protein sequestering activity / negative regulation of innate immune response / protein export from nucleus / release of cytochrome c from mitochondria / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / positive regulation of protein export from nucleus / negative regulation of protein kinase activity / stem cell proliferation / Translocation of SLC2A4 (GLUT4) to the plasma membrane / TP53 Regulates Metabolic Genes / transcription coregulator activity / Downregulation of SMAD2/3:SMAD4 transcriptional activity / negative regulation of canonical Wnt signaling pathway / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / multicellular organism growth / positive regulation of protein localization to nucleus / intrinsic apoptotic signaling pathway in response to DNA damage / transcription corepressor activity / osteoblast differentiation / protein localization / regulation of protein localization / positive regulation of cell growth / transcription regulator complex / transcription coactivator activity / regulation of cell cycle / protein ubiquitination / nuclear body / cadherin binding / positive regulation of cell population proliferation / regulation of DNA-templated transcription / protein kinase binding / negative regulation of transcription by RNA polymerase II / signal transduction / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / extracellular space / extracellular exosome / nucleoplasm / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
: / 14-3-3 domain / Delta-Endotoxin; domain 1 / 14-3-3 protein sigma / WW domain / WW/rsp5/WWP domain signature. / WW domain superfamily / WW/rsp5/WWP domain profile. / Domain with 2 conserved Trp (W) residues / WW domain ...: / 14-3-3 domain / Delta-Endotoxin; domain 1 / 14-3-3 protein sigma / WW domain / WW/rsp5/WWP domain signature. / WW domain superfamily / WW/rsp5/WWP domain profile. / Domain with 2 conserved Trp (W) residues / WW domain / 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 / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
5-azanyl-4-phenyl-thiophene-2-carboximidamide / 14-3-3 protein sigma / WW domain-containing transcription regulator protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.2 Å
AuthorsGenet, S. / Wolter, M. / Guillory, X. / Somsen, B. / Leysen, S. / Castaldi, P. / Ottmann, C.
Funding support Netherlands, 1items
OrganizationGrant numberCountry
European Commission Netherlands
CitationJournal: J.Med.Chem. / Year: 2020
Title: Fragment-based Differential Targeting of PPI Stabilizer Interfaces.
Authors: Guillory, X. / Wolter, M. / Leysen, S. / Neves, J.F. / Kuusk, A. / Genet, S. / Somsen, B. / Morrow, J.K. / Rivers, E. / van Beek, L. / Patel, J. / Goodnow, R. / Schoenherr, H. / Fuller, N. / ...Authors: Guillory, X. / Wolter, M. / Leysen, S. / Neves, J.F. / Kuusk, A. / Genet, S. / Somsen, B. / Morrow, J.K. / Rivers, E. / van Beek, L. / Patel, J. / Goodnow, R. / Schoenherr, H. / Fuller, N. / Cao, Q. / Doveston, R.G. / Brunsveld, L. / Arkin, M.R. / Castaldi, P. / Boyd, H. / Landrieu, I. / Chen, H. / Ottmann, C.
History
DepositionApr 19, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 17, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 22, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.name
Revision 1.2Jan 24, 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 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / refine / struct_conn / struct_conn_type
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _refine.pdbx_diffrn_id / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_ptnr2_label_alt_id / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn.ptnr2_symmetry / _struct_conn_type.id
Revision 1.3Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 14-3-3 protein sigma
P: WW domain-containing transcription regulator protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,3268
Polymers27,9652
Non-polymers3616
Water5,296294
1
A: 14-3-3 protein sigma
P: WW domain-containing transcription regulator protein 1
hetero molecules

A: 14-3-3 protein sigma
P: WW domain-containing transcription regulator protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,65316
Polymers55,9314
Non-polymers72212
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area6610 Å2
ΔGint-106 kcal/mol
Surface area22230 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.025, 112.307, 62.697
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z+1/2
#4: -x,-y,z+1/2
#5: x+1/2,y+1/2,z
#6: x+1/2,-y+1/2,-z
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,z+1/2
Components on special symmetry positions
IDModelComponents
11A-302-

MG

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AP

#1: Protein 14-3-3 protein sigma / Epithelial cell marker protein 1 / Stratifin


Mass: 26542.914 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SFN, HME1 / Production host: Escherichia coli (E. coli) / References: UniProt: P31947
#2: Protein/peptide WW domain-containing transcription regulator protein 1 / Transcriptional coactivator with PDZ-binding motif


Mass: 1422.439 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q9GZV5

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Non-polymers , 4 types, 300 molecules

#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-K48 / 5-azanyl-4-phenyl-thiophene-2-carboximidamide


Mass: 217.290 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H11N3S / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 294 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.67 Å3/Da / Density % sol: 53.99 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: Protein and peptide were mixed at a 1:2 molar stoichiometry with a final protein concentration of 12 mg/mL in crystallization buffer. This was used during hanging-drop crystallization in a 1: ...Details: Protein and peptide were mixed at a 1:2 molar stoichiometry with a final protein concentration of 12 mg/mL in crystallization buffer. This was used during hanging-drop crystallization in a 1:1 ratio with 0.1 M HEPES pH 7.5, 0.2 M CaCl2, 5% glycerol, 2 mM BME and 28% PEG400. Crystals were grown within 10 days at 4 C and fragment soaking was performed on crystals of 10 days and older by adding 0.2 uL of a 100 mM stock solution in dimethyl sulfoxide to 2 uL drops containing multiple crystals.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, DESY / Beamline: P11 / Wavelength: 1.033191 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Oct 28, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.033191 Å / Relative weight: 1
ReflectionResolution: 1.2→41.83 Å / Num. obs: 89802 / % possible obs: 99.3 % / Redundancy: 12.8 % / CC1/2: 0.997 / Rrim(I) all: 0.113 / Net I/σ(I): 11.3
Reflection shellResolution: 1.2→1.22 Å / Redundancy: 12.8 % / Mean I/σ(I) obs: 2.1 / Num. unique obs: 4345 / CC1/2: 0.575 / Rrim(I) all: 0.937 / % possible all: 97.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
DIALSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3MHR

3mhr


Resolution: 1.2→41.83 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.967 / SU B: 0.684 / SU ML: 0.029 / Cross valid method: THROUGHOUT / ESU R: 0.038 / ESU R Free: 0.039 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.19674 4541 5.1 %RANDOM
Rwork0.18124 ---
obs0.182 85244 99.32 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 14.636 Å2
Baniso -1Baniso -2Baniso -3
1-0.57 Å20 Å2-0 Å2
2---0.17 Å20 Å2
3----0.4 Å2
Refinement stepCycle: LAST / Resolution: 1.2→41.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1869 0 20 294 2183
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0132013
X-RAY DIFFRACTIONr_bond_other_d0.0010.0171894
X-RAY DIFFRACTIONr_angle_refined_deg1.9121.6462733
X-RAY DIFFRACTIONr_angle_other_deg1.6031.5814416
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3395269
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.75222.524103
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.86915383
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.4171514
X-RAY DIFFRACTIONr_chiral_restr0.1050.2264
X-RAY DIFFRACTIONr_gen_planes_refined0.010.022286
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02408
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_it1.4251.309995
X-RAY DIFFRACTIONr_mcbond_other1.4241.308994
X-RAY DIFFRACTIONr_mcangle_it2.1431.9531249
X-RAY DIFFRACTIONr_mcangle_other2.1421.9531250
X-RAY DIFFRACTIONr_scbond_it2.5241.5671018
X-RAY DIFFRACTIONr_scbond_other2.5231.5671019
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.8062.2541471
X-RAY DIFFRACTIONr_long_range_B_refined4.96617.1582467
X-RAY DIFFRACTIONr_long_range_B_other4.64916.2922381
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.2→1.231 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.35 348 -
Rwork0.362 6113 -
obs--97.58 %

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