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- PDB-4kab: FOCAL ADHESION KINASE CATALYTIC DOMAIN IN COMPLEX WITH 3-Methyl-1... -

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Basic information

Entry
Database: PDB / ID: 4kab
TitleFOCAL ADHESION KINASE CATALYTIC DOMAIN IN COMPLEX WITH 3-Methyl-1,4-dihydro-pyrazolo[4,5-c]pyrazole
ComponentsFocal adhesion kinase 1PTK2
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 / positive regulation of ubiquitin-dependent protein catabolic process / JUN kinase binding / signal complex assembly / positive regulation of macrophage proliferation / positive regulation of fibroblast migration ...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 / positive regulation of ubiquitin-dependent protein catabolic process / JUN kinase binding / signal complex assembly / positive regulation of macrophage proliferation / positive regulation of fibroblast migration / DCC mediated attractive signaling / Signal regulatory protein family interactions / growth hormone receptor signaling pathway / regulation of osteoblast differentiation / regulation of cytoskeleton organization / MET activates PTK2 signaling / regulation of focal adhesion assembly / establishment of cell polarity / positive regulation of wound healing / positive regulation of macrophage chemotaxis / regulation of GTPase activity / Fc-gamma receptor signaling pathway involved in phagocytosis / p130Cas linkage to MAPK signaling for integrins / positive regulation of epithelial cell migration / negative regulation of cell-cell adhesion / Apoptotic cleavage of cellular proteins / regulation of cell adhesion mediated by integrin / GRB2:SOS provides linkage to MAPK signaling for Integrins / negative regulation of anoikis / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / RHO GTPases Activate WASPs and WAVEs / positive regulation of epithelial to mesenchymal transition / ephrin receptor signaling pathway / positive regulation of protein kinase activity / vascular endothelial growth factor receptor signaling pathway / regulation of cell adhesion / heart morphogenesis / stress fiber / EPHB-mediated forward signaling / NCAM signaling for neurite out-growth / SH2 domain binding / Integrin signaling / transforming growth factor beta receptor signaling pathway / ciliary basal body / placenta development / protein tyrosine phosphatase activity / molecular function activator activity / cell motility / integrin-mediated signaling pathway / axon guidance / FCGR3A-mediated phagocytosis / regulation of protein phosphorylation / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / epidermal growth factor receptor signaling pathway / Regulation of actin dynamics for phagocytic cup formation / VEGFA-VEGFR2 Pathway / peptidyl-tyrosine phosphorylation / cell migration / integrin binding / actin binding / regulation of cell population proliferation / cell cortex / regulation of cell shape / RAF/MAP kinase cascade / protein phosphatase binding / angiogenesis / protein tyrosine kinase activity / dendritic spine / Extra-nuclear estrogen signaling / protein autophosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / cytoskeleton / positive regulation of cell migration / positive regulation of protein phosphorylation / focal adhesion / intracellular membrane-bounded organelle / centrosome / positive regulation of cell population proliferation / negative regulation of apoptotic process / protein kinase binding / perinuclear region of cytoplasm / ATP binding / nucleus / plasma membrane / cytosol / cytoplasm
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. / PH-like domain superfamily / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Ubiquitin-like domain superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-methyl-1,5-dihydropyrazolo[4,3-c]pyrazole / Focal adhesion kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.71 Å
AuthorsMusil, D. / Graedler, U. / Heinrich, T. / Lehmann, M. / Dresing, V.
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 22, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 11, 2013Provider: repository / Type: Initial release
Revision 1.1Oct 9, 2013Group: Database references

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)64,1604
Polymers63,9162
Non-polymers2442
Water1,29772
1
A: Focal adhesion kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,0802
Polymers31,9581
Non-polymers1221
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Focal adhesion kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,0802
Polymers31,9581
Non-polymers1221
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)45.960, 88.590, 136.890
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 / PTK2 / 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, UNP residues 410-686
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTK2, FAK, FAK1 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: Q05397, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-4KA / 3-methyl-1,5-dihydropyrazolo[4,3-c]pyrazole


Mass: 122.128 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C5H6N4
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 72 / 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: 2.18 Å3/Da / Density % sol: 43.58 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 0.1 M sodium citrate, 18% PEG MME 2000, pH 6.0, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Aug 15, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.71→44.3 Å / Num. all: 15794 / Num. obs: 15718 / % possible obs: 99.5 % / Observed criterion σ(I): -3 / Redundancy: 4.7 % / Biso Wilson estimate: 56.3 Å2 / Rmerge(I) obs: 0.095 / Net I/σ(I): 14.4
Reflection shellResolution: 2.71→2.88 Å / Redundancy: 4.8 % / Rmerge(I) obs: 0.483 / Mean I/σ(I) obs: 3.5 / Num. unique all: 2459 / % possible all: 98.4

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Processing

Software
NameVersionClassification
PHASERphasing
BUSTER2.11.4refinement
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.71→44.3 Å / Cor.coef. Fo:Fc: 0.9365 / Cor.coef. Fo:Fc free: 0.9052 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2194 786 5 %RANDOM
Rwork0.1706 ---
obs0.173 15718 99.32 %-
Displacement parametersBiso mean: 47.88 Å2
Baniso -1Baniso -2Baniso -3
1-7.4295 Å20 Å20 Å2
2---6.4297 Å20 Å2
3----0.9998 Å2
Refine analyzeLuzzati coordinate error obs: 0.328 Å
Refinement stepCycle: LAST / Resolution: 2.71→44.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4131 0 18 72 4221
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014244HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.15737HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1496SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes98HARMONIC2
X-RAY DIFFRACTIONt_gen_planes606HARMONIC5
X-RAY DIFFRACTIONt_it4244HARMONIC20
X-RAY DIFFRACTIONt_omega_torsion3.04
X-RAY DIFFRACTIONt_other_torsion19.69
X-RAY DIFFRACTIONt_chiral_improper_torsion545SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact4746SEMIHARMONIC4
LS refinement shellResolution: 2.71→2.9 Å / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.302 135 4.97 %
Rwork0.1908 2581 -
all0.196 2716 -
obs--99.32 %
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)
11.9940.6122-1.04241.7947-1.37182.81740.01520.37420.1811-0.12420.06690.057-0.0192-0.3516-0.0821-0.13140.0615-0.0028-0.06950.0818-0.1576-14.361619.5615-34.4676
21.82430.4893-0.32772.2351-0.84821.74-0.0072-0.09520.02090.04050.09760.04520.1186-0.0507-0.0903-0.0370.018-0.0473-0.12020.0192-0.143-5.3779-0.5012-3.0546
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|412 - A|686 }A412 - 686
2X-RAY DIFFRACTION2{ B|414 - B|684 }B414 - 684

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