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- PDB-6rp6: Fragment AZ-019 binding at the TAZpS89/14-3-3 sigma interface -

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Basic information

Entry
Database: PDB / ID: 6rp6
TitleFragment AZ-019 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 / Physiological factors / RUNX3 regulates YAP1-mediated transcription / mesenchymal cell differentiation / YAP1- and WWTR1 (TAZ)-stimulated gene expression / heart process / stem cell division / hippo signaling / tissue homeostasis ...kidney morphogenesis / regulation of metanephric nephron tubule epithelial cell differentiation / Physiological factors / RUNX3 regulates YAP1-mediated transcription / mesenchymal cell differentiation / YAP1- and WWTR1 (TAZ)-stimulated gene expression / heart process / stem cell division / hippo signaling / tissue homeostasis / EGR2 and SOX10-mediated initiation of Schwann cell myelination / SMAD protein signal transduction / glomerulus development / Signaling by Hippo / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / negative regulation of fat cell differentiation / regulation of epidermal cell division / protein kinase C inhibitor activity / positive regulation of epidermal cell differentiation / keratinocyte development / keratinization / RUNX2 regulates osteoblast differentiation / Regulation of localization of FOXO transcription factors / keratinocyte proliferation / phosphoserine residue binding / cilium assembly / Activation of BAD and translocation to mitochondria / negative regulation of keratinocyte proliferation / establishment of skin barrier / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / positive regulation of osteoblast differentiation / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / positive regulation of epithelial to mesenchymal transition / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / negative regulation of stem cell proliferation / RHO GTPases activate PKNs / protein kinase A signaling / protein sequestering activity / negative regulation of innate immune response / protein export from nucleus / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / positive regulation of protein export from nucleus / release of cytochrome c from mitochondria / negative regulation of protein phosphorylation / stem cell proliferation / Translocation of SLC2A4 (GLUT4) to the plasma membrane / TP53 Regulates Metabolic Genes / Downregulation of SMAD2/3:SMAD4 transcriptional activity / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / negative regulation of protein kinase activity / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / negative regulation of canonical Wnt signaling pathway / multicellular organism growth / positive regulation of protein localization to nucleus / osteoblast differentiation / transcription corepressor activity / intrinsic apoptotic signaling pathway in response to DNA damage / positive regulation of cell growth / transcription regulator complex / transcription coactivator activity / nuclear body / regulation of cell cycle / protein ubiquitination / 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 / cytoplasm / cytosol
Similarity search - Function
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 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
Similarity search - Domain/homology
Chem-KDK / 14-3-3 protein sigma / WW domain-containing transcription regulator protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.885 Å
AuthorsGenet, S. / Wolter, M. / Guillory, X. / Somsen, B. / Leysen, S. / Patel, J. / 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
DepositionMay 14, 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 / 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_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.ptnr1_symmetry / _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 / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_ptnr1_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

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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)28,3285
Polymers27,9652
Non-polymers3633
Water6,053336
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)56,65610
Polymers55,9314
Non-polymers7256
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area5570 Å2
ΔGint-73 kcal/mol
Surface area22920 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.970, 112.020, 62.790
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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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, 339 molecules

#3: Chemical ChemComp-KDK / 4-phenyl-5-(piperidin-4-ylmethyl)thiophene-2-carboximidamide


Mass: 299.434 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H21N3S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#5: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 336 / 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: 2.43 Å3/Da / Density % sol: 49.4 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.1
Details: 0.095 M Na-HEPES pH 7.1, 27% PEG400, 0.19 M Calcium chloride, 5% Glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SEALED TUBE / Type: RIGAKU MICROMAX-003 / Wavelength: 1.54187 Å
DetectorType: DECTRIS PILATUS 200K / Detector: PIXEL / Date: Aug 2, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54187 Å / Relative weight: 1
ReflectionResolution: 1.62→41.86 Å / Num. obs: 31371 / % possible obs: 83.4 % / Redundancy: 5.6 % / CC1/2: 0.998 / Rrim(I) all: 0.082 / Net I/σ(I): 14
Reflection shellResolution: 1.62→1.64 Å / Redundancy: 1.2 % / Mean I/σ(I) obs: 1.1 / Num. unique obs: 111 / CC1/2: 0.862 / Rrim(I) all: 0.391 / % possible all: 6.1

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575: ???)refinement
REFMACrefinement
MOSFLMdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3MHR

3mhr


Resolution: 1.885→25.576 Å / SU ML: 0.19 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 20.73
RfactorNum. reflection% reflection
Rfree0.2201 1180 4.98 %
Rwork0.1568 --
obs0.1598 23682 99.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.885→25.576 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1886 0 23 336 2245
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.012012
X-RAY DIFFRACTIONf_angle_d0.9532724
X-RAY DIFFRACTIONf_dihedral_angle_d12.6461242
X-RAY DIFFRACTIONf_chiral_restr0.047299
X-RAY DIFFRACTIONf_plane_restr0.006357
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.885-1.97080.25491410.20352761X-RAY DIFFRACTION100
1.9708-2.07460.27291420.17832784X-RAY DIFFRACTION100
2.0746-2.20450.23171500.15792756X-RAY DIFFRACTION100
2.2045-2.37470.20641640.1442766X-RAY DIFFRACTION100
2.3747-2.61340.20371450.14762819X-RAY DIFFRACTION100
2.6134-2.99110.24341420.15892825X-RAY DIFFRACTION100
2.9911-3.76650.20291510.13842830X-RAY DIFFRACTION100
3.7665-25.57870.20191450.16112961X-RAY DIFFRACTION100

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