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- PDB-6hp9: Structure of the kinase domain of human DDR1 in complex with a 2-... -

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Basic information

Entry
Database: PDB / ID: 6hp9
TitleStructure of the kinase domain of human DDR1 in complex with a 2-Amino-2,3-Dihydro-1H-Indene-5-Carboxamide-based inhibitor
ComponentsEpithelial discoidin domain-containing receptor 1
KeywordsTRANSFERASE / DDR1 / Structural Genomics / Structural Genomics Consortium / SGC
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 / protein autophosphorylation / receptor complex / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / 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-GKB / Epithelial discoidin domain-containing receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.96 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. / Structural Genomics Consortium (SGC)
CitationJournal: J.Med.Chem. / Year: 2019
Title: 2-Amino-2,3-dihydro-1H-indene-5-carboxamide-Based Discoidin Domain Receptor 1 (DDR1) Inhibitors: Design, Synthesis, and in Vivo Antipancreatic Cancer Efficacy.
Authors: Zhu, D. / Huang, H. / Pinkas, D.M. / Luo, J. / Ganguly, D. / Fox, A.E. / Arner, E. / Xiang, Q. / Tu, Z.C. / Bullock, A.N. / Brekken, R.A. / Ding, K. / Lu, X.
History
DepositionSep 19, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 30, 2019Provider: repository / Type: Initial release
Revision 1.1Jul 31, 2019Group: 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
Revision 1.2Sep 4, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.3Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
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)72,4654
Polymers71,5082
Non-polymers9572
Water6,738374
1
A: Epithelial discoidin domain-containing receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,2332
Polymers35,7541
Non-polymers4781
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Epithelial discoidin domain-containing receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,2332
Polymers35,7541
Non-polymers4781
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)62.510, 65.890, 162.880
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 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-GKB / (2~{R})-~{N}-[3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl]-2-(pyrimidin-5-ylamino)-2,3-dihydro-1~{H}-indene-5-carboxamide


Mass: 478.469 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C25H21F3N6O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 374 / 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: 2.4 Å3/Da / Density % sol: 48.79 %
Crystal growTemperature: 277 K / Method: vapor diffusion
Details: 1:2 protein to mother liquor Protein: 12 mg/ml in 50 mM HEPES pH 7.5, 300 mM NaCl, 0.5 mM TCEP, 2% DMSO, 1 mM compound Mother liquor: 25% PEG 1500

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Sep 10, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.96→61.1 Å / Num. obs: 49094 / % possible obs: 99.76 % / Redundancy: 6.5 % / Net I/σ(I): 8
Reflection shellResolution: 1.96→2.03 Å

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Processing

Software
NameVersionClassification
PHENIX(1.13_2998: ???)refinement
xia2data reduction
xia2data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6GWR
Resolution: 1.96→61.081 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 30.75
RfactorNum. reflection% reflection
Rfree0.2507 2361 4.81 %
Rwork0.2046 --
obs0.2069 49056 99.77 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.96→61.081 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4597 0 70 374 5041
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0074779
X-RAY DIFFRACTIONf_angle_d0.8356481
X-RAY DIFFRACTIONf_dihedral_angle_d18.5382905
X-RAY DIFFRACTIONf_chiral_restr0.049699
X-RAY DIFFRACTIONf_plane_restr0.006901
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.96-20.41671420.36432691X-RAY DIFFRACTION100
2-2.04350.40911190.32682685X-RAY DIFFRACTION100
2.0435-2.0910.36171510.32712X-RAY DIFFRACTION100
2.091-2.14330.32281390.27282727X-RAY DIFFRACTION100
2.1433-2.20130.32971380.2522691X-RAY DIFFRACTION100
2.2013-2.26610.27931260.25242719X-RAY DIFFRACTION100
2.2661-2.33920.27881150.23242732X-RAY DIFFRACTION100
2.3392-2.42280.30671240.22332733X-RAY DIFFRACTION100
2.4228-2.51980.28671490.21432734X-RAY DIFFRACTION100
2.5198-2.63450.29421240.21682744X-RAY DIFFRACTION100
2.6345-2.77340.27661470.20752713X-RAY DIFFRACTION100
2.7734-2.94720.24751300.21042760X-RAY DIFFRACTION100
2.9472-3.17470.26291620.21342742X-RAY DIFFRACTION100
3.1747-3.49420.26531460.19532772X-RAY DIFFRACTION100
3.4942-3.99970.19641320.16682777X-RAY DIFFRACTION100
3.9997-5.03880.18081590.15492826X-RAY DIFFRACTION100
5.0388-61.11110.21521580.19082937X-RAY DIFFRACTION100

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