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- PDB-6rw2: Bicycle Toxin Conjugate bound to EphA2 -

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Basic information

Entry
Database: PDB / ID: 6rw2
TitleBicycle Toxin Conjugate bound to EphA2
Components
  • ALA-ARG-ASP-CYS-PRO-LEU-VAL-ASN-PRO-LEU-CYS-LEU-HIS-PRO-GLY-TRP-THR-CYS
  • Ephrin type-A receptor 2
KeywordsSIGNALING PROTEIN / EphA2 / inhibitor / complex
Function / homology
Function and homology information


notochord cell development / notochord formation / lens fiber cell morphogenesis / blood vessel endothelial cell proliferation involved in sprouting angiogenesis / negative regulation of lymphangiogenesis / axial mesoderm formation / pericyte cell differentiation / cAMP metabolic process / positive regulation of bicellular tight junction assembly / regulation of blood vessel endothelial cell migration ...notochord cell development / notochord formation / lens fiber cell morphogenesis / blood vessel endothelial cell proliferation involved in sprouting angiogenesis / negative regulation of lymphangiogenesis / axial mesoderm formation / pericyte cell differentiation / cAMP metabolic process / positive regulation of bicellular tight junction assembly / regulation of blood vessel endothelial cell migration / leading edge membrane / negative regulation of chemokine production / bone remodeling / transmembrane-ephrin receptor activity / post-anal tail morphogenesis / response to growth factor / activation of GTPase activity / regulation of lamellipodium assembly / tight junction / branching involved in mammary gland duct morphogenesis / EPH-Ephrin signaling / neural tube development / RND1 GTPase cycle / RND2 GTPase cycle / RND3 GTPase cycle / mammary gland epithelial cell proliferation / RHOV GTPase cycle / EPHA-mediated growth cone collapse / growth factor binding / regulation of cell adhesion mediated by integrin / lamellipodium membrane / RHOU GTPase cycle / RHOG GTPase cycle / EPH-ephrin mediated repulsion of cells / RAC2 GTPase cycle / ephrin receptor signaling pathway / RAC3 GTPase cycle / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / vasculogenesis / regulation of angiogenesis / keratinocyte differentiation / RAC1 GTPase cycle / transmembrane receptor protein tyrosine kinase activity / cell chemotaxis / negative regulation of angiogenesis / osteoclast differentiation / regulation of ERK1 and ERK2 cascade / phosphatidylinositol 3-kinase/protein kinase B signal transduction / skeletal system development / molecular function activator activity / protein localization to plasma membrane / cell motility / positive regulation of protein localization to plasma membrane / axon guidance / receptor protein-tyrosine kinase / ruffle membrane / osteoblast differentiation / intrinsic apoptotic signaling pathway in response to DNA damage / cell migration / virus receptor activity / lamellipodium / receptor complex / cell adhesion / positive regulation of cell migration / defense response to Gram-positive bacterium / cadherin binding / inflammatory response / phosphorylation / focal adhesion / dendrite / cell surface / ATP binding / plasma membrane
Similarity search - Function
Ephrin type-A receptor 2, ligand binding domain / Ephrin receptor type-A /type-B / Ephrin receptor ligand binding domain / Tyrosine-protein kinase, receptor class V, conserved site / Ephrin receptor, transmembrane domain / Ephrin receptor ligand binding domain / Ephrin type-A receptor 2 transmembrane domain / Receptor tyrosine kinase class V signature 1. / Receptor tyrosine kinase class V signature 2. / Eph receptor ligand-binding domain profile. ...Ephrin type-A receptor 2, ligand binding domain / Ephrin receptor type-A /type-B / Ephrin receptor ligand binding domain / Tyrosine-protein kinase, receptor class V, conserved site / Ephrin receptor, transmembrane domain / Ephrin receptor ligand binding domain / Ephrin type-A receptor 2 transmembrane domain / Receptor tyrosine kinase class V signature 1. / Receptor tyrosine kinase class V signature 2. / Eph receptor ligand-binding domain profile. / Ephrin receptor ligand binding domain / Putative ephrin-receptor like / SAM domain (Sterile alpha motif) / Galactose-binding domain-like / SAM domain profile. / Sterile alpha motif. / Sterile alpha motif domain / Sterile alpha motif/pointed domain superfamily / Growth factor receptor cysteine-rich domain superfamily / Fibronectin type III domain / Fibronectin type 3 domain / Fibronectin type-III domain profile. / Galactose-binding-like domain superfamily / Fibronectin type III / Fibronectin type III superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Jelly Rolls / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / Sandwich / Mainly Beta
Similarity search - Domain/homology
Chem-29N / Ephrin type-A receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.26 Å
AuthorsBrown, D.G. / Schroeder, S. / Chen, L.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Identification and Optimization of EphA2-Selective Bicycles for the Delivery of Cytotoxic Payloads.
Authors: Mudd, G.E. / Brown, A. / Chen, L. / van Rietschoten, K. / Watcham, S. / Teufel, D.P. / Pavan, S. / Lani, R. / Huxley, P. / Bennett, G.S.
History
DepositionJun 3, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 8, 2020Provider: repository / Type: Initial release
Revision 1.1Apr 22, 2020Group: Database references / Category: citation / citation_author
Item: _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2May 6, 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.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Ephrin type-A receptor 2
B: ALA-ARG-ASP-CYS-PRO-LEU-VAL-ASN-PRO-LEU-CYS-LEU-HIS-PRO-GLY-TRP-THR-CYS
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,3514
Polymers24,0042
Non-polymers3472
Water77543
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2050 Å2
ΔGint-15 kcal/mol
Surface area9810 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.090, 113.680, 130.960
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222

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Components

#1: Protein Ephrin type-A receptor 2 / Epithelial cell kinase / Tyrosine-protein kinase receptor ECK


Mass: 22006.697 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EPHA2, ECK / Production host: Escherichia coli (E. coli)
References: UniProt: P29317, receptor protein-tyrosine kinase
#2: Protein/peptide ALA-ARG-ASP-CYS-PRO-LEU-VAL-ASN-PRO-LEU-CYS-LEU-HIS-PRO-GLY-TRP-THR-CYS


Mass: 1997.366 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-29N / 1,1',1''-(1,3,5-triazinane-1,3,5-triyl)tripropan-1-one / 1,1',1''-(1,3,5-triazinane-1,3,5-triyl)triprop-2-en-1-one, bound form


Mass: 255.313 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H21N3O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 43 / 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: 3.55 Å3/Da / Density % sol: 65.39 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.1M sodium acetate 0.2M lithium sulphate 8-10% PEG 6000
PH range: 5.5-5.75

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 3, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.26→58.64 Å / Num. obs: 15014 / % possible obs: 98.7 % / Redundancy: 5.8 % / Rmerge(I) obs: 0.077 / Net I/σ(I): 15.8
Reflection shellResolution: 2.26→2.33 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.935 / Num. unique obs: 667 / % possible all: 87.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
PDB_EXTRACT3.22data extraction
xia2data reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.26→56.9 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.903 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.225 / ESU R Free: 0.207
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2646 780 5.2 %RANDOM
Rwork0.211 ---
obs0.2138 14234 98.68 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 131.32 Å2 / Biso mean: 41.752 Å2 / Biso min: 20.17 Å2
Baniso -1Baniso -2Baniso -3
1--1.2 Å2-0 Å2-0 Å2
2--1.55 Å2-0 Å2
3----0.35 Å2
Refinement stepCycle: final / Resolution: 2.26→56.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1546 0 24 43 1613
Biso mean--52.66 48.04 -
Num. residues----193
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0131637
X-RAY DIFFRACTIONr_bond_other_d0.0350.0171471
X-RAY DIFFRACTIONr_angle_refined_deg2.0191.6582221
X-RAY DIFFRACTIONr_angle_other_deg3.0681.63406
X-RAY DIFFRACTIONr_dihedral_angle_1_deg9.5825195
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.24422.04588
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.74415262
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.9631510
X-RAY DIFFRACTIONr_chiral_restr0.0880.2199
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.021848
X-RAY DIFFRACTIONr_gen_planes_other0.0170.02366
X-RAY DIFFRACTIONr_mcbond_it3.6444.285780
X-RAY DIFFRACTIONr_mcbond_other3.6444.285779
X-RAY DIFFRACTIONr_mcangle_it5.6276.416975
LS refinement shellResolution: 2.26→2.319 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.341 54 -
Rwork0.34 934 -
all-988 -
obs--88.61 %

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