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- PDB-4ihl: Human 14-3-3 isoform zeta in complex with a diphoyphorylated C-RA... -

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Basic information

Entry
Database: PDB / ID: 4ihl
TitleHuman 14-3-3 isoform zeta in complex with a diphoyphorylated C-RAF peptide and Cotylenin A
Components
  • 14-3-3 protein zeta/delta
  • RAF proto-oncogene serine/threonine-protein kinase
KeywordsPEPTIDE BINDING PROTEIN / 14-3-3 FOLD / RAF / ALL ALPHA-HELICAL / ADAPTER PROTEIN / PROTEIN-PROTEIN INTERACTION
Function / homology
Function and homology information


death-inducing signaling complex assembly / Golgi reassembly / synaptic target recognition / regulation of synapse maturation / NOTCH4 Activation and Transmission of Signal to the Nucleus / respiratory system process / intermediate filament cytoskeleton organization / establishment of Golgi localization / type B pancreatic cell proliferation / regulation of Rho protein signal transduction ...death-inducing signaling complex assembly / Golgi reassembly / synaptic target recognition / regulation of synapse maturation / NOTCH4 Activation and Transmission of Signal to the Nucleus / respiratory system process / intermediate filament cytoskeleton organization / establishment of Golgi localization / type B pancreatic cell proliferation / regulation of Rho protein signal transduction / tube formation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / Rap1 signalling / regulation of cell motility / insulin secretion involved in cellular response to glucose stimulus / negative regulation of protein localization to nucleus / Negative feedback regulation of MAPK pathway / KSRP (KHSRP) binds and destabilizes mRNA / IFNG signaling activates MAPKs / GP1b-IX-V activation signalling / ERBB2-ERBB3 signaling pathway / regulation of cell differentiation / face development / pseudopodium / somatic stem cell population maintenance / thyroid gland development / neurotrophin TRK receptor signaling pathway / Regulation of localization of FOXO transcription factors / extrinsic apoptotic signaling pathway via death domain receptors / Interleukin-3, Interleukin-5 and GM-CSF signaling / phosphoserine residue binding / MAP kinase kinase kinase activity / Activation of BAD and translocation to mitochondria / protein targeting / negative regulation of protein-containing complex assembly / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / cellular response to glucose starvation / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / Schwann cell development / type II interferon-mediated signaling pathway / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / RHO GTPases activate PKNs / negative regulation of TORC1 signaling / activation of adenylate cyclase activity / response to muscle stretch / ERK1 and ERK2 cascade / myelination / negative regulation of innate immune response / protein sequestering activity / CD209 (DC-SIGN) signaling / hippocampal mossy fiber to CA3 synapse / regulation of ERK1 and ERK2 cascade / insulin-like growth factor receptor signaling pathway / thymus development / Translocation of SLC2A4 (GLUT4) to the plasma membrane / Deactivation of the beta-catenin transactivating complex / TP53 Regulates Metabolic Genes / Negative regulation of NOTCH4 signaling / RAF activation / lung development / Signaling by high-kinase activity BRAF mutants / wound healing / MAP2K and MAPK activation / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / regulation of protein stability / Stimuli-sensing channels / Negative regulation of MAPK pathway / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / MAPK cascade / Signaling by BRAF and RAF1 fusions / melanosome / insulin receptor signaling pathway / positive regulation of peptidyl-serine phosphorylation / regulation of apoptotic process / DNA-binding transcription factor binding / angiogenesis / vesicle / mitochondrial outer membrane / transmembrane transporter binding / positive regulation of MAPK cascade / blood microparticle / non-specific serine/threonine protein kinase / protein kinase activity / cadherin binding / protein domain specific binding / negative regulation of cell population proliferation / protein phosphorylation / protein serine kinase activity / focal adhesion / protein serine/threonine kinase activity / glutamatergic synapse / apoptotic process / ubiquitin protein ligase binding / negative regulation of apoptotic process / protein kinase binding
Similarity search - Function
14-3-3 domain / Raf-like Ras-binding domain / Raf-like Ras-binding / Ras-binding domain (RBD) profile. / Raf-like Ras-binding domain / Delta-Endotoxin; domain 1 / Diacylglycerol/phorbol-ester binding / Phorbol esters/diacylglycerol binding domain (C1 domain) / Zinc finger phorbol-ester/DAG-type signature. / Zinc finger phorbol-ester/DAG-type profile. ...14-3-3 domain / Raf-like Ras-binding domain / Raf-like Ras-binding / Ras-binding domain (RBD) profile. / Raf-like Ras-binding domain / Delta-Endotoxin; domain 1 / Diacylglycerol/phorbol-ester binding / Phorbol esters/diacylglycerol binding domain (C1 domain) / Zinc finger phorbol-ester/DAG-type signature. / Zinc finger phorbol-ester/DAG-type profile. / Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains) / Protein kinase C-like, phorbol ester/diacylglycerol-binding domain / C1-like domain superfamily / 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 / Ubiquitin-like domain superfamily / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-1F5 / : / RAF proto-oncogene serine/threonine-protein kinase / 14-3-3 protein zeta/delta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MIR / Resolution: 2.2 Å
AuthorsMolzan, M. / Ottmann, C.
CitationJournal: Acs Chem.Biol. / Year: 2013
Title: Stabilization of Physical RAF/14-3-3 Interaction by Cotylenin A as Treatment Strategy for RAS Mutant Cancers.
Authors: Molzan, M. / Kasper, S. / Roglin, L. / Skwarczynska, M. / Sassa, T. / Inoue, T. / Breitenbuecher, F. / Ohkanda, J. / Kato, N. / Schuler, M. / Ottmann, C.
History
DepositionDec 19, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 25, 2013Provider: repository / Type: Initial release
Revision 1.1Oct 9, 2013Group: Database references
Revision 1.2Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_entity_nonpoly / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _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_label_asym_id / _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.value / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _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_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: 14-3-3 protein zeta/delta
B: 14-3-3 protein zeta/delta
P: RAF proto-oncogene serine/threonine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,9487
Polymers57,6253
Non-polymers1,3244
Water5,296294
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5030 Å2
ΔGint-32 kcal/mol
Surface area22650 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.280, 103.400, 112.580
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 26720.217 Da / Num. of mol.: 2 / Fragment: UNP residues 1-230
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: YWHAZ / Plasmid: PPROEX HTB / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta (DE3) / References: UniProt: P63104
#2: Protein/peptide RAF proto-oncogene serine/threonine-protein kinase / Proto-oncogene c-RAF / cRaf / Raf-1


Mass: 4184.204 Da / Num. of mol.: 1 / Fragment: UNP residues 229-264 / Source method: obtained synthetically
Details: synthetic peptide, The full-lenth C-Raf kinase occurs in homo spaiens
Source: (synth.) Homo sapiens (human)
References: UniProt: P04049, non-specific serine/threonine protein kinase
#3: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: K
#4: Chemical ChemComp-1F5 / (1R,3aS,4R,5R,6R,9aR,10E)-6-({(1S,2R,4S,5R,6R,8S,9S)-5-hydroxy-2-(methoxymethyl)-9-methyl-9-[(2S)-oxiran-2-yl]-3,7,10,1 1-tetraoxatricyclo[6.2.1.0~1,6~]undec-4-yl}oxy)-1-(methoxymethyl)-4,9a-dimethyl-7-(propan-2-yl)-1,2,3,3a,4,5,6,8,9,9a-de cahydrodicyclopenta[a,d][8]annulene-1,5-diol / Cotylenin A


Mass: 622.743 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C33H50O11
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 294 / 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: 3.66 Å3/Da / Density % sol: 66.37 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 0.1 M NA-ACETATE PH 7.0, 0.8 M NAH2PO4 AND 1.2 M K2HPO4, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9778 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Oct 6, 2010
RadiationMonochromator: AL2/AL2 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9778 Å / Relative weight: 1
ReflectionResolution: 2.2→49.4 Å / Num. all: 43603 / Num. obs: 42870 / % possible obs: 98.3 % / Observed criterion σ(F): -3 / Observed criterion σ(I): -3 / Biso Wilson estimate: 48.794 Å2 / Rmerge(I) obs: 0.035 / Net I/σ(I): 21.65
Reflection shell

Diffraction-ID: 1

Resolution (Å)Highest resolution (Å)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. unique obs% possible all
2.2-2.30.284.6619090520497.5
2.3-2.40.2076.5717363440997.8
2.4-2.50.1647.8714545374597.9
2.5-30.08313.61459841222898.5
3-40.0332.5936669983598.9
4-60.02246.8718894516698.7
6-100.0250.156153175698.5
10-120.01953.1666020993.7
120.01953.62106031895.5

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
REFMACrefinement
PDB_EXTRACT3.11data extraction
XDSdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MIR
Starting model: PDB ENTRY 4FJ3

4fj3


Resolution: 2.2→49.4 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.941 / WRfactor Rfree: 0.2455 / WRfactor Rwork: 0.2006 / Occupancy max: 1 / Occupancy min: 0 / FOM work R set: 0.8288 / SU B: 4.988 / SU ML: 0.126 / SU R Cruickshank DPI: 0.1923 / SU Rfree: 0.1776 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.192 / ESU R Free: 0.178 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2432 2142 5 %RANDOM
Rwork0.2002 ---
all0.2024 43603 --
obs0.2024 42823 98.34 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 143.15 Å2 / Biso mean: 50.1522 Å2 / Biso min: 24.11 Å2
Baniso -1Baniso -2Baniso -3
1--1.22 Å20 Å20 Å2
2--3.55 Å20 Å2
3----2.33 Å2
Refinement stepCycle: LAST / Resolution: 2.2→49.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3762 0 90 294 4146
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0224076
X-RAY DIFFRACTIONr_angle_refined_deg1.57525554
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.555514
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.00525.123203
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.77315.039763
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.3361528
X-RAY DIFFRACTIONr_chiral_restr0.1030.2630
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.023022
LS refinement shellResolution: 2.2→2.257 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.341 138 -
Rwork0.262 2740 -
all-2878 -
obs--96.93 %

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