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- PDB-4k8a: Fragment-based discovery of Focal Adhesion Kinase Inhibitors -

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Basic information

Entry
Database: PDB / ID: 4k8a
TitleFragment-based discovery of Focal Adhesion Kinase Inhibitors
ComponentsFocal adhesion kinase 1
KeywordsTransferase/Transferase Inhibitor / TYROSINE PROTEIN KINASE / TRANSFERASE / ATP BINDING / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


netrin-activated signaling pathway / regulation of substrate adhesion-dependent cell spreading / regulation of endothelial cell migration / regulation of epithelial cell migration / detection of muscle stretch / JUN kinase binding / signal complex assembly / positive regulation of ubiquitin-dependent protein catabolic process / positive regulation of macrophage proliferation / DCC mediated attractive signaling ...netrin-activated signaling pathway / regulation of substrate adhesion-dependent cell spreading / regulation of endothelial cell migration / regulation of epithelial cell migration / detection of muscle stretch / JUN kinase binding / signal complex assembly / positive regulation of ubiquitin-dependent protein catabolic process / positive regulation of macrophage proliferation / DCC mediated attractive signaling / positive regulation of fibroblast migration / Signal regulatory protein family interactions / regulation of GTPase activity / growth hormone receptor signaling pathway / MET activates PTK2 signaling / regulation of focal adhesion assembly / negative regulation of cell-cell adhesion / positive regulation of wound healing / p130Cas linkage to MAPK signaling for integrins / regulation of osteoblast differentiation / Apoptotic cleavage of cellular proteins / establishment of cell polarity / positive regulation of macrophage chemotaxis / regulation of cytoskeleton organization / regulation of cell adhesion mediated by integrin / Fc-gamma receptor signaling pathway involved in phagocytosis / vascular endothelial cell response to oscillatory fluid shear stress / GRB2:SOS provides linkage to MAPK signaling for Integrins / regulation of protein phosphorylation / negative regulation of anoikis / positive regulation of epithelial cell migration / ephrin receptor signaling pathway / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / RHO GTPases Activate WASPs and WAVEs / positive regulation of protein kinase activity / vascular endothelial growth factor receptor signaling pathway / regulation of cell adhesion / positive regulation of epithelial to mesenchymal transition / heart morphogenesis / stress fiber / EPHB-mediated forward signaling / Integrin signaling / protein tyrosine phosphatase activity / NCAM signaling for neurite out-growth / transforming growth factor beta receptor signaling pathway / SH2 domain binding / axon guidance / molecular function activator activity / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / integrin-mediated signaling pathway / non-membrane spanning protein tyrosine kinase activity / FCGR3A-mediated phagocytosis / non-specific protein-tyrosine kinase / cell motility / placenta development / peptidyl-tyrosine phosphorylation / Regulation of actin dynamics for phagocytic cup formation / VEGFA-VEGFR2 Pathway / epidermal growth factor receptor signaling pathway / integrin binding / cell migration / regulation of cell shape / regulation of cell population proliferation / positive regulation of protein phosphorylation / actin binding / RAF/MAP kinase cascade / cell cortex / protein autophosphorylation / protein tyrosine kinase activity / protein phosphatase binding / angiogenesis / cytoskeleton / Extra-nuclear estrogen signaling / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / ciliary basal body / cilium / positive regulation of cell migration / focal adhesion / intracellular membrane-bounded organelle / positive regulation of cell population proliferation / centrosome / negative regulation of apoptotic process / protein kinase binding / perinuclear region of cytoplasm / ATP binding / nucleus / plasma membrane / cytosol
Similarity search - Function
Focal adhesion kinase, targeting (FAT) domain / Focal adhesion kinase, targeting (FAT) domain superfamily / Focal adhesion kinase, N-terminal / FAK1/PYK2, FERM domain C-lobe / Focal adhesion targeting region / FERM N-terminal domain / : / FAK1/PYK2, FERM domain C-lobe / FERM domain signature 2. / FERM central domain ...Focal adhesion kinase, targeting (FAT) domain / Focal adhesion kinase, targeting (FAT) domain superfamily / Focal adhesion kinase, N-terminal / FAK1/PYK2, FERM domain C-lobe / Focal adhesion targeting region / FERM N-terminal domain / : / FAK1/PYK2, FERM domain C-lobe / FERM domain signature 2. / FERM central domain / FERM/acyl-CoA-binding protein superfamily / FERM central domain / FERM superfamily, second domain / FERM domain / FERM domain profile. / Band 4.1 domain / Band 4.1 homologues / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / PH-like domain superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Ubiquitin-like domain superfamily / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / 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
3-bromo-5-(2H-tetrazol-5-yl)pyridine / Focal adhesion kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.91 Å
AuthorsGraedler, U. / Bomke, J. / Musil, D. / Dresing, V. / Lehmann, M. / Hoelzemann, G. / Esdar, C. / Krier, M. / Heinrich, T.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Fragment-based discovery of focal adhesion kinase inhibitors.
Authors: Gradler, U. / Bomke, J. / Musil, D. / Dresing, V. / Lehmann, M. / Holzemann, G. / Greiner, H. / Esdar, C. / Krier, M. / Heinrich, T.
History
DepositionApr 18, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 11, 2013Provider: repository / Type: Initial release
Revision 1.1Oct 9, 2013Group: Database references
Revision 1.2Dec 27, 2023Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_conn / struct_conn_type / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Focal adhesion kinase 1
B: Focal adhesion kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,3684
Polymers63,9162
Non-polymers4522
Water37821
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Focal adhesion kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,1842
Polymers31,9581
Non-polymers2261
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
A: Focal adhesion kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,1842
Polymers31,9581
Non-polymers2261
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)47.070, 88.559, 137.087
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 Focal adhesion kinase 1 / FADK 1 / Focal adhesion kinase-related nonkinase / FRNK / Protein phosphatase 1 regulatory subunit ...FADK 1 / Focal adhesion kinase-related nonkinase / FRNK / Protein phosphatase 1 regulatory subunit 71 / PPP1R71 / Protein-tyrosine kinase 2 / p125FAK / pp125FAK


Mass: 31957.928 Da / Num. of mol.: 2 / Fragment: KINASE DOMAIN, RESIDUES 410-686
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FAK, FAK1, PTK2 / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): Hi5
References: UniProt: Q05397, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-K8A / 3-bromo-5-(2H-tetrazol-5-yl)pyridine


Mass: 226.033 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H4BrN5
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 21 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.24 Å3/Da / Density % sol: 44.97 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 0.1M NaCitrat 6.0, 20% PEG MME 550, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Jun 9, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.91→42.14 Å / Num. obs: 12993 / % possible obs: 96.1 % / Observed criterion σ(F): -3 / Observed criterion σ(I): -3 / Redundancy: 2 % / Biso Wilson estimate: 64.48 Å2 / Rsym value: 0.081 / Net I/σ(I): 8.69
Reflection shellResolution: 2.91→3.08 Å / Redundancy: 1.95 % / Rmerge(I) obs: 0.41 / Mean I/σ(I) obs: 2.29 / % possible all: 91.2

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Processing

Software
NameVersionClassification
XDSdata scaling
MOLREPphasing
BUSTER2.11.4refinement
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.91→42.14 Å / Cor.coef. Fo:Fc: 0.9269 / Cor.coef. Fo:Fc free: 0.8964 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2235 650 5 %RANDOM
Rwork0.1821 ---
obs0.1842 12993 98.6 %-
Displacement parametersBiso mean: 55.98 Å2
Baniso -1Baniso -2Baniso -3
1--0.4711 Å20 Å20 Å2
2---3.0268 Å20 Å2
3---3.4979 Å2
Refine analyzeLuzzati coordinate error obs: 0.38 Å
Refinement stepCycle: LAST / Resolution: 2.91→42.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4095 0 24 21 4140
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0094215HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.995699HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1481SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes96HARMONIC2
X-RAY DIFFRACTIONt_gen_planes602HARMONIC5
X-RAY DIFFRACTIONt_it4215HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion
X-RAY DIFFRACTIONt_other_torsion
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion
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_contact
LS refinement shellResolution: 2.91→3.14 Å / Total num. of bins used: 7
RfactorNum. reflection% reflection
Rfree0.2619 130 4.98 %
Rwork0.2162 2478 -
all0.2186 2608 -
obs--98.6 %
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)
12.1862-1.24551.15071.6476-1.0953.2224-0.0309-0.2981-0.12320.07820.0620.0466-0.0315-0.3592-0.0311-0.1623-0.05830.03980.02870.0456-0.1868-14.753-19.907134.3676
21.5151-0.85620.18162.6538-0.51880.99820.03940.16320.12830.04610.0129-0.075-0.0994-0.0213-0.0523-0.1008-0.03530.02210.00340.0187-0.1665-5.5910.52473.107
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|414 - A|683 }A414 - 683
2X-RAY DIFFRACTION2{ B|414 - B|684 }B414 - 684

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