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- PDB-5bvo: Fragment-based discovery of potent and selective DDR1/2 inhibitors -

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Basic information

Entry
Database: PDB / ID: 5bvo
TitleFragment-based discovery of potent and selective DDR1/2 inhibitors
ComponentsEpithelial discoidin domain-containing receptor 1
KeywordsTRANSFERASE / DDR1 / fragments
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 / collagen binding / lactation / embryo implantation / transmembrane receptor protein tyrosine kinase activity / regulation of cell growth / receptor protein-tyrosine kinase / positive regulation of neuron projection development / cell population proliferation / protein autophosphorylation / 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-4VE / IODIDE ION / Epithelial discoidin domain-containing receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.98 Å
AuthorsMurray, C. / Berdini, V. / Buck, I. / Carr, M. / Cleasby, A. / Coyle, J. / Curry, J. / Day, J. / Hearn, K. / Iqbal, A. ...Murray, C. / Berdini, V. / Buck, I. / Carr, M. / Cleasby, A. / Coyle, J. / Curry, J. / Day, J. / Hearn, K. / Iqbal, A. / Lee, L. / Martins, V. / Mortenson, P. / Munck, J. / Page, L. / Patel, S. / Roomans, S. / Kirsten, T. / Saxty, G.
CitationJournal: Acs Med.Chem.Lett. / Year: 2015
Title: Fragment-Based Discovery of Potent and Selective DDR1/2 Inhibitors.
Authors: Murray, C.W. / Berdini, V. / Buck, I.M. / Carr, M.E. / Cleasby, A. / Coyle, J.E. / Curry, J.E. / Day, J.E. / Day, P.J. / Hearn, K. / Iqbal, A. / Lee, L.Y. / Martins, V. / Mortenson, P.N. / ...Authors: Murray, C.W. / Berdini, V. / Buck, I.M. / Carr, M.E. / Cleasby, A. / Coyle, J.E. / Curry, J.E. / Day, J.E. / Day, P.J. / Hearn, K. / Iqbal, A. / Lee, L.Y. / Martins, V. / Mortenson, P.N. / Munck, J.M. / Page, L.W. / Patel, S. / Roomans, S. / Smith, K. / Tamanini, E. / Saxty, G.
History
DepositionJun 5, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Aug 5, 2015Provider: repository / Type: Initial release
Revision 1.1May 8, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)37,7549
Polymers36,4361
Non-polymers1,3188
Water4,720262
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1080 Å2
ΔGint-2 kcal/mol
Surface area14310 Å2
MethodPISA
Unit cell
Length a, b, c (Å)61.921, 78.360, 75.732
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 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: 36435.785 Da / Num. of mol.: 1 / Fragment: residues 576-894
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DDR1, CAK, EDDR1, NEP, NTRK4, PTK3A, RTK6, TRKE / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q08345, receptor protein-tyrosine kinase
#2: Chemical
ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: I
#3: Chemical ChemComp-4VE / N-(5-{(1S)-1-[(5-fluoro-1,3-benzoxazol-2-yl)amino]ethyl}-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide


Mass: 429.446 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H20FN5O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 262 / 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: 2.52 Å3/Da / Density % sol: 51.22 %
Crystal growTemperature: 277 K / Method: vapor diffusion / Details: 17.4%w/v PEG 3350, 0.2M NH4I

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.92 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 22, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 1.98→78 Å / Num. obs: 24693 / % possible obs: 99 % / Redundancy: 6.6 % / Net I/σ(I): 11

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Processing

Software
NameVersionClassification
SCALAdata scaling
REFMAC5.8.0107refinement
PDB_EXTRACT3.15data extraction
XDSdata reduction
RefinementResolution: 1.98→48.58 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.927 / SU B: 8.604 / SU ML: 0.136 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.164 / ESU R Free: 0.159 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.2459 1312 5 %RANDOM
Rwork0.1948 ---
obs0.1974 24693 98.78 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 132.85 Å2 / Biso mean: 44.129 Å2 / Biso min: 16.41 Å2
Baniso -1Baniso -2Baniso -3
1--2.21 Å2-0 Å20 Å2
2--1.8 Å2-0 Å2
3---0.42 Å2
Refinement stepCycle: final / Resolution: 1.98→48.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2226 0 59 262 2547
Biso mean--38.82 49.03 -
Num. residues----276
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0192310
X-RAY DIFFRACTIONr_bond_other_d0.0030.02520
X-RAY DIFFRACTIONr_angle_refined_deg1.411.9523123
X-RAY DIFFRACTIONr_angle_other_deg0.4811.17141
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8265272
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.01323.009117
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.95415396
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.1041522
X-RAY DIFFRACTIONr_chiral_restr0.0960.2335
X-RAY DIFFRACTIONr_gen_planes_refined0.0010.0211766
X-RAY DIFFRACTIONr_gen_planes_other0.0050.04413
X-RAY DIFFRACTIONr_mcbond_it1.5514.2491100
X-RAY DIFFRACTIONr_scbond_it2.1334.8021210
LS refinement shellResolution: 1.98→2.031 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.307 86 -
Rwork0.302 1758 -
all-1844 -
obs--95.84 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.8549-2.64662.28142.9454-0.07063.4965-0.5426-0.33490.59780.20820.4581-0.5432-0.78810.06270.08450.41570.0220.07630.3584-0.01470.298626.439543.502640.1535
22.97970.65420.03682.2789-0.83092.16270.09260.1031-0.1077-0.0882-0.0156-0.0258-0.0079-0.1994-0.0770.01060.0171-0.00040.30920.00550.007714.368921.235130.117
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A604 - 703
2X-RAY DIFFRACTION2A704 - 911

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