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

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Basic information

Entry
Database: PDB / ID: 5bvw
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-1N1 / IODIDE ION / Epithelial discoidin domain-containing receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.94 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

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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)37,93910
Polymers36,4361
Non-polymers1,5039
Water5,170287
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2080 Å2
ΔGint-4 kcal/mol
Surface area14060 Å2
MethodPISA
Unit cell
Length a, b, c (Å)61.642, 72.780, 75.787
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: resideus 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.: 8 / Source method: obtained synthetically / Formula: I
#3: Chemical ChemComp-1N1 / N-(2-CHLORO-6-METHYLPHENYL)-2-({6-[4-(2-HYDROXYETHYL)PIPERAZIN-1-YL]-2-METHYLPYRIMIDIN-4-YL}AMINO)-1,3-THIAZOLE-5-CARBOXAMIDE / Dasatinib


Mass: 488.006 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H26ClN7O2S / Comment: medication*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 287 / 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: 2.33 Å3/Da / Density % sol: 47.28 %
Crystal growTemperature: 277 K / Method: vapor diffusion / Details: 18.0%w/v PEG 3350, 0.2M NH4I

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.976 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 22, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 1.9→33 Å / Num. obs: 25196 / % possible obs: 97 % / Redundancy: 2.7 % / Rmerge(I) obs: 0.056 / Net I/σ(I): 8.6
Reflection shellResolution: 1.94→2.02 Å / Rmerge(I) obs: 0.468 / Mean I/σ(I) obs: 1.6 / % possible all: 97.4

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Processing

Software
NameVersionClassification
MOSFLMdata reduction
SCALAdata scaling
REFMAC2.11.6refinement
PDB_EXTRACT3.15data extraction
Aimlessdata scaling
PHASERphasing
RefinementResolution: 1.94→32.8 Å / Cor.coef. Fo:Fc: 0.9534 / Cor.coef. Fo:Fc free: 0.9352 / SU R Cruickshank DPI: 0.147 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.163 / SU Rfree Blow DPI: 0.152 / SU Rfree Cruickshank DPI: 0.144
RfactorNum. reflection% reflectionSelection details
Rfree0.2335 1266 5.02 %RANDOM
Rwork0.1836 ---
obs0.1862 25195 97.35 %-
Displacement parametersBiso max: 149.07 Å2 / Biso mean: 45.088 Å2 / Biso min: 16.11 Å2
Baniso -1Baniso -2Baniso -3
1-4.5594 Å20 Å20 Å2
2---3.1554 Å20 Å2
3----1.404 Å2
Refine analyzeLuzzati coordinate error obs: 0.244 Å
Refinement stepCycle: final / Resolution: 1.94→32.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2212 0 41 287 2540
Biso mean--41.41 56.56 -
Num. residues----274
LS refinement shellResolution: 1.94→2.02 Å / Total num. of bins used: 13
RfactorNum. reflection% reflection
Rfree0.2488 121 4.28 %
Rwork0.2201 2708 -
all0.2212 2829 -
obs--98.5 %
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)
12.3617-1.11460.19881.44690.89433.4541-0.3121-0.03030.23130.07160.118-0.2047-0.42740.18330.19410.0137-0.012-0.0006-0.13580.01520.004326.74741.584839.7873
22.00450.21890.32741.1413-0.2781.77290.063-0.1168-0.1015-0.1091-0.0344-0.06740.0347-0.1337-0.0286-0.10060.01540.0146-0.03860.0188-0.055714.991719.160129.7458
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|604 - A|703 }A604 - 703
2X-RAY DIFFRACTION2{ A|704 - A|911 }A704 - 911

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