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- PDB-6fex: DDR1, 2-[4-bromo-2-oxo-1'-(1H-pyrazolo[4,3-b]pyridine-5-carbonyl)... -

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Basic information

Entry
Database: PDB / ID: 6fex
TitleDDR1, 2-[4-bromo-2-oxo-1'-(1H-pyrazolo[4,3-b]pyridine-5-carbonyl)spiro[indole-3,4'-piperidine]-1-yl]-N-(2,2,2-trifluoroethyl)acetamide, 1.291A, P212121, Rfree=17.4%
ComponentsEpithelial discoidin domain-containing receptor 1
KeywordsTRANSFERASE / RTK / RECEPTOR TYROSINE KINASE / COLLAGEN / DISCOIDIN DOMAIN
Function / homology
Function and homology information


protein tyrosine kinase collagen receptor activity / smooth muscle cell-matrix adhesion / regulation of extracellular matrix disassembly / regulation of cell-matrix adhesion / ear development / collagen-activated tyrosine kinase receptor signaling pathway / branching involved in mammary gland duct morphogenesis / wound healing, spreading of cells / smooth muscle cell migration / neuron projection extension ...protein tyrosine kinase collagen receptor activity / smooth muscle cell-matrix adhesion / regulation of extracellular matrix disassembly / regulation of cell-matrix adhesion / ear development / collagen-activated tyrosine kinase receptor signaling pathway / branching involved in mammary gland duct morphogenesis / wound healing, spreading of cells / smooth muscle cell migration / neuron projection extension / axon development / Non-integrin membrane-ECM interactions / mammary gland alveolus development / peptidyl-tyrosine autophosphorylation / embryo implantation / collagen binding / lactation / transmembrane receptor protein tyrosine kinase activity / regulation of cell growth / positive regulation of neuron projection development / receptor protein-tyrosine kinase / cell surface receptor protein tyrosine kinase signaling pathway / cell population proliferation / protein autophosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / cell adhesion / negative regulation of cell population proliferation / extracellular space / extracellular exosome / ATP binding / metal ion binding / plasma membrane
Similarity search - Function
: / Discoidin domain-containing receptor 1/2, DS-like domain / Coagulation factors 5/8 type C domain (FA58C) signature 2. / Coagulation factors 5/8 type C domain (FA58C) signature 1. / Coagulation factor 5/8 C-terminal domain, discoidin domain / Coagulation factors 5/8 type C domain (FA58C) profile. / F5/8 type C domain / Coagulation factor 5/8 C-terminal domain / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. ...: / Discoidin domain-containing receptor 1/2, DS-like domain / Coagulation factors 5/8 type C domain (FA58C) signature 2. / Coagulation factors 5/8 type C domain (FA58C) signature 1. / Coagulation factor 5/8 C-terminal domain, discoidin domain / Coagulation factors 5/8 type C domain (FA58C) profile. / F5/8 type C domain / Coagulation factor 5/8 C-terminal domain / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Galactose-binding-like domain 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-D6Z / IODIDE ION / Epithelial discoidin domain-containing receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.291 Å
AuthorsStihle, M. / Richter, H. / Benz, J. / Kuhn, B. / Rudolph, M.G.
CitationJournal: Acs Chem.Biol. / Year: 2019
Title: DNA-Encoded Library-Derived DDR1 Inhibitor Prevents Fibrosis and Renal Function Loss in a Genetic Mouse Model of Alport Syndrome.
Authors: Richter, H. / Satz, A.L. / Bedoucha, M. / Buettelmann, B. / Petersen, A.C. / Harmeier, A. / Hermosilla, R. / Hochstrasser, R. / Burger, D. / Gsell, B. / Gasser, R. / Huber, S. / Hug, M.N. / ...Authors: Richter, H. / Satz, A.L. / Bedoucha, M. / Buettelmann, B. / Petersen, A.C. / Harmeier, A. / Hermosilla, R. / Hochstrasser, R. / Burger, D. / Gsell, B. / Gasser, R. / Huber, S. / Hug, M.N. / Kocer, B. / Kuhn, B. / Ritter, M. / Rudolph, M.G. / Weibel, F. / Molina-David, J. / Kim, J.J. / Santos, J.V. / Stihle, M. / Georges, G.J. / Bonfil, R.D. / Fridman, R. / Uhles, S. / Moll, S. / Faul, C. / Fornoni, A. / Prunotto, M.
History
DepositionJan 3, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 28, 2018Provider: repository / Type: Initial release
Revision 1.1Mar 27, 2019Group: Data collection / Database references / Category: citation / pdbx_database_proc
Item: _citation.journal_abbrev / _citation.journal_volume ..._citation.journal_abbrev / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation.year
SupersessionDec 16, 2020ID: 6FIM
Revision 1.2Dec 16, 2020Group: Advisory / Category: pdbx_database_PDB_obs_spr

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Epithelial discoidin domain-containing receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,91311
Polymers36,5031
Non-polymers1,41010
Water6,053336
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1550 Å2
ΔGint-36 kcal/mol
Surface area14600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)40.834, 61.750, 63.072
Angle α, β, γ (deg.)90.000, 106.510, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Epithelial discoidin domain-containing receptor 1 / Epithelial discoidin domain receptor 1 / CD167 antigen-like family member A / Cell adhesion kinase ...Epithelial discoidin domain receptor 1 / CD167 antigen-like family member A / Cell adhesion kinase / Discoidin receptor tyrosine kinase / HGK2 / Mammary carcinoma kinase 10 / MCK-10 / Protein-tyrosine kinase 3A / Protein-tyrosine kinase RTK-6 / TRK E / Tyrosine kinase DDR / Tyrosine-protein kinase CAK


Mass: 36502.855 Da / Num. of mol.: 1 / Fragment: tyrosine kinase domain, residues 593-913
Mutation: DEL(730-735) 2-[4-bromo-2-oxo-1'-(1H-pyrazolo[4,3-b]pyridine-5-carbonyl)spiro[indole-3,4'-piperidine]-1-yl]-N-(2,2,2-trifluoroethyl)acetamide
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DDR1, CAK, EDDR1, NEP, NTRK4, PTK3A, RTK6, TRKE / Plasmid: pFastBac1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q08345, receptor protein-tyrosine kinase

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Non-polymers , 5 types, 346 molecules

#2: Chemical ChemComp-D6Z / 2-[4-bromanyl-2-oxidanylidene-1'-(1~{H}-pyrazolo[4,3-b]pyridin-5-ylcarbonyl)spiro[indole-3,4'-piperidine]-1-yl]-~{N}-[2,2,2-tris(fluoranyl)ethyl]ethanamide


Mass: 565.343 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H20BrF3N6O3
#3: Chemical
ChemComp-IOD / IODIDE ION / Iodide


Mass: 126.904 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: I
#4: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID / MES (buffer)


Mass: 195.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#5: Chemical
ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water / 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: 2.09 Å3/Da / Density % sol: 41.11 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 11.3 mg/mL protein in 20mM HEPES/NaOH pH7.5, 5mM DTT, 5% glycerol, 0.1M NaCl mixed 1.3:1 with 90mM MES/NaOH pH6.5, 0.18M potassium iodide, 0.2M Li2SO4, 22.5% PEG 4K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99999 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 9, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength
IDWavelength (Å)Relative weight
10.999991
211
ReflectionResolution: 1.33→61.75 Å / Num. obs: 67043 / % possible obs: 97.2 % / Observed criterion σ(I): -3 / Redundancy: 3.71 % / Biso Wilson estimate: 12.05 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.071 / Rrim(I) all: 0.083 / Rsym value: 0.071 / Χ2: 1.025 / Net I/σ(I): 8.35 / Num. measured all: 252733
Reflection shellResolution: 1.33→1.42 Å / Redundancy: 3.46 % / Rmerge(I) obs: 0.747 / Mean I/σ(I) obs: 1.05 / Num. measured obs: 3080 / Num. possible: 818 / Num. unique obs: 810 / CC1/2: 0.999 / Rrim(I) all: 0.032 / Rsym value: 0.747 / Rejects: 0 / % possible all: 94.4

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
PHENIX1.12rc1_2801refinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: inhouse model

Resolution: 1.291→60.472 Å / SU ML: 0.13 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 20.49 / Stereochemistry target values: ML
Details: bromine partially radiolyzed. anomalous peak ca 10A next to bromine could in principle also be bromine atom, but since iodide was present in the mother liquor, no decision can be made based on densities.
RfactorNum. reflection% reflectionSelection details
Rfree0.1737 2839 4.99 %random
Rwork0.1374 54071 --
obs0.1392 56910 75.53 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 92.79 Å2 / Biso mean: 20.8042 Å2 / Biso min: 6.04 Å2
Refinement stepCycle: final / Resolution: 1.291→60.472 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2337 0 89 336 2762
Biso mean--19.73 29.19 -
Num. residues----289
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092504
X-RAY DIFFRACTIONf_angle_d1.1013403
X-RAY DIFFRACTIONf_chiral_restr0.082358
X-RAY DIFFRACTIONf_plane_restr0.007440
X-RAY DIFFRACTIONf_dihedral_angle_d18.484988
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.2911-1.31340.356450.24921171223
1.3134-1.33730.455780.20762812898
1.3373-1.3630.3234360.209965569118
1.363-1.39080.2863650.22551161122633
1.3908-1.42110.2489880.21781677176547
1.4211-1.45410.29581250.21232357248266
1.4541-1.49050.25791480.19832682283075
1.4905-1.53080.23361480.18763026317485
1.5308-1.57580.25131710.17333400357194
1.5758-1.62670.21361750.14733455363097
1.6267-1.68480.22271750.13323448362397
1.6848-1.75230.18991830.13133473365697
1.7523-1.83210.18181720.11893513368598
1.8321-1.92870.15971730.11773490366398
1.9287-2.04950.13761940.11493539373398
2.0495-2.20780.1682260.11333456368298
2.2078-2.42990.1441750.1173571374699
2.4299-2.78150.15862020.12633522372499
2.7815-3.50440.16561830.13593607379099
3.5044-60.53830.15531870.14943641382899

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