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- PDB-6gwr: Structure of the kinase domain of human DDR1 in complex with a po... -

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Basic information

Entry
Database: PDB / ID: 6gwr
TitleStructure of the kinase domain of human DDR1 in complex with a potent and selective inhibitor of DDR1 and DDR2
ComponentsEpithelial discoidin domain-containing receptor 1
KeywordsTRANSFERASE
Function / homology
Function and homology information


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 / neuron projection extension / smooth muscle cell migration / axon development ...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 / neuron projection extension / smooth muscle cell migration / axon development / Non-integrin membrane-ECM interactions / mammary gland alveolus development / peptidyl-tyrosine autophosphorylation / collagen binding / transmembrane receptor protein tyrosine kinase activity / lactation / embryo implantation / cell surface receptor protein tyrosine kinase signaling pathway / regulation of cell growth / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / positive regulation of neuron projection development / protein autophosphorylation / cell population proliferation / 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-FEW / Epithelial discoidin domain-containing receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.07 Å
AuthorsPinkas, D.M. / Fox, A.E. / Kupinska, K. / Burgess-Brown, N.A. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Bullock, A.N.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Design, Synthesis, and Biological Evaluation of 3-(Imidazo[1,2- a]pyrazin-3-ylethynyl)-4-isopropyl- N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide as a Dual ...Title: Design, Synthesis, and Biological Evaluation of 3-(Imidazo[1,2- a]pyrazin-3-ylethynyl)-4-isopropyl- N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide as a Dual Inhibitor of Discoidin Domain Receptors 1 and 2.
Authors: Wang, Z. / Zhang, Y. / Pinkas, D.M. / Fox, A.E. / Luo, J. / Huang, H. / Cui, S. / Xiang, Q. / Xu, T. / Xun, Q. / Zhu, D. / Tu, Z. / Ren, X. / Brekken, R.A. / Bullock, A.N. / Liang, G. / Ding, K. / Lu, X.
History
DepositionJun 25, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 8, 2018Provider: repository / Type: Initial release
Revision 1.1Aug 15, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.name
Revision 1.2Aug 29, 2018Group: Data collection / Database references / Structure summary
Category: citation / citation_author / struct_keywords
Item: _citation.title / _citation_author.identifier_ORCID ..._citation.title / _citation_author.identifier_ORCID / _citation_author.name / _struct_keywords.pdbx_keywords / _struct_keywords.text
Revision 1.3Sep 26, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.4May 15, 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
B: Epithelial discoidin domain-containing receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,13725
Polymers71,5082
Non-polymers2,62923
Water11,512639
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5950 Å2
ΔGint-28 kcal/mol
Surface area28300 Å2
MethodPISA
Unit cell
Length a, b, c (Å)43.200, 118.750, 61.430
Angle α, β, γ (deg.)90.00, 92.05, 90.00
Int Tables number4
Space group name H-MP1211

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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: 35754.094 Da / Num. of mol.: 2
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-FEW / 3-(2-imidazo[1,2-a]pyrazin-3-ylethynyl)-~{N}-[3-[(4-methylpiperazin-1-yl)methyl]-5-(trifluoromethyl)phenyl]-4-propan-2-yl-benzamide


Mass: 560.613 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C31H31F3N6O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 15 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 639 / 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: 2.2 Å3/Da / Density % sol: 44.14 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 10% ethylene glycol -- 0.2M sodium sulfate -- 24% PEG3350 -- 0.1M bis-tris-propane pH 7.1

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9762 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: May 19, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9762 Å / Relative weight: 1
ReflectionResolution: 2.07→30.7 Å / Num. obs: 69417 / % possible obs: 98.6 % / Redundancy: 1.8 % / Net I/σ(I): 6.12
Reflection shellResolution: 2.07→2.14 Å

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Processing

Software
NameVersionClassification
PHENIX(1.13_2998: ???)refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.07→30.695 Å / SU ML: 0.26 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 26.16
RfactorNum. reflection% reflection
Rfree0.2372 1871 5.04 %
Rwork0.2006 --
obs0.2024 37126 98.6 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.07→30.695 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4640 0 172 639 5451
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0034914
X-RAY DIFFRACTIONf_angle_d0.5886634
X-RAY DIFFRACTIONf_dihedral_angle_d19.7012908
X-RAY DIFFRACTIONf_chiral_restr0.041702
X-RAY DIFFRACTIONf_plane_restr0.004849
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.0701-2.1260.311330.30742692X-RAY DIFFRACTION98
2.126-2.18860.37431570.29382665X-RAY DIFFRACTION98
2.1886-2.25920.33041590.28982690X-RAY DIFFRACTION98
2.2592-2.33990.29121380.25232638X-RAY DIFFRACTION97
2.3399-2.43360.26191440.23422723X-RAY DIFFRACTION99
2.4336-2.54430.27171300.22132748X-RAY DIFFRACTION99
2.5443-2.67830.25881420.20682696X-RAY DIFFRACTION99
2.6783-2.8460.22751440.20322712X-RAY DIFFRACTION99
2.846-3.06560.23751430.19452751X-RAY DIFFRACTION99
3.0656-3.37380.22041720.18192674X-RAY DIFFRACTION99
3.3738-3.86110.17021220.16052765X-RAY DIFFRACTION99
3.8611-4.86150.19631380.15972741X-RAY DIFFRACTION99
4.8615-30.69870.24961490.21192760X-RAY DIFFRACTION99

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