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

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Basic information

Entry
Database: PDB / ID: 5bvn
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-4VD / IODIDE ION / Epithelial discoidin domain-containing receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.21 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 12, 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)36,9803
Polymers36,4361
Non-polymers5442
Water3,081171
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area130 Å2
ΔGint-1 kcal/mol
Surface area13840 Å2
MethodPISA
Unit cell
Length a, b, c (Å)61.040, 78.497, 74.499
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.: 1 / Source method: obtained synthetically / Formula: I
#3: Chemical ChemComp-4VD / N-[5-({[(3-fluorophenyl)carbamoyl]amino}methyl)-2-methylphenyl]imidazo[1,2-a]pyridine-3-carboxamide


Mass: 417.436 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H20FN5O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 171 / 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: 2.45 Å3/Da / Density % sol: 49.78 %
Crystal growTemperature: 277 K / Method: vapor diffusion / Details: 10.0%w/v PEG 3350, 0.1M KNO3

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.54187 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: Mar 16, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54187 Å / Relative weight: 1
ReflectionResolution: 2.2→78 Å / Num. obs: 16924 / % possible obs: 96 % / Redundancy: 3.9 % / Net I/σ(I): 3.4

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
BUSTERBUSTER 2.11.6refinement
SCALAdata scaling
PHASERphasing
PDB_EXTRACT3.15data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.21→31.8 Å / Cor.coef. Fo:Fc: 0.8246 / Cor.coef. Fo:Fc free: 0.765 / SU R Cruickshank DPI: 0.314 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.34 / SU Rfree Blow DPI: 0.279 / SU Rfree Cruickshank DPI: 0.271
RfactorNum. reflection% reflectionSelection details
Rfree0.3275 918 5.17 %RANDOM
Rwork0.2523 ---
obs0.2562 17755 95.95 %-
Displacement parametersBiso max: 111.22 Å2 / Biso mean: 29.02 Å2 / Biso min: 3 Å2
Baniso -1Baniso -2Baniso -3
1-6.7519 Å20 Å20 Å2
2---8.174 Å20 Å2
3---1.4221 Å2
Refine analyzeLuzzati coordinate error obs: 0.379 Å
Refinement stepCycle: final / Resolution: 2.21→31.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2245 0 52 171 2468
Biso mean--24.44 26.61 -
Num. residues----278
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d819SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes59HARMONIC2
X-RAY DIFFRACTIONt_gen_planes352HARMONIC16
X-RAY DIFFRACTIONt_it2349HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion283SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3072SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2349HARMONIC20.012
X-RAY DIFFRACTIONt_angle_deg3189HARMONIC21.2
X-RAY DIFFRACTIONt_omega_torsion7.2
X-RAY DIFFRACTIONt_other_torsion20.34
LS refinement shellResolution: 2.21→2.34 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.3025 130 4.66 %
Rwork0.2249 2658 -
all0.2286 2788 -
obs--94.61 %
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)
10.6658-0.7451-0.66870.61720.67070.0466-0.0373-0.0340.012-0.01510.0449-0.0168-0.05890.0157-0.00770.01910.0092-0.0051-0.2618-0.00640.209526.092143.107339.6748
22.00250.63110.19071.6351-0.39371.63750.0332-0.0191-0.0818-0.12460.038-0.0783-0.045-0.0394-0.0713-0.08220.04780.0175-0.28190.02190.103613.999721.217929.5091
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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