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- PDB-4gu6: FOCAL ADHESION KINASE CATALYTIC DOMAIN IN COMPLEX WITH N-{3-[(5-C... -

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Basic information

Entry
Database: PDB / ID: 4gu6
TitleFOCAL ADHESION KINASE CATALYTIC DOMAIN IN COMPLEX WITH N-{3-[(5-Cyano-2-phenyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)- methyl]-pyridin-2-yl}-N-methyl-methanesulfonamide
ComponentsFocal adhesion kinase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Protein tyrosine kinase / 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 cell-cell adhesion mediated by integrin / JUN kinase binding / signal complex assembly / negative regulation of cell adhesion mediated by integrin / positive regulation of macrophage proliferation ...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 cell-cell adhesion mediated by integrin / JUN kinase binding / signal complex assembly / negative regulation of cell adhesion mediated by integrin / positive regulation of macrophage proliferation / DCC mediated attractive signaling / Signal regulatory protein family interactions / positive regulation of fibroblast migration / positive regulation of ubiquitin-dependent protein catabolic process / MET activates PTK2 signaling / growth hormone receptor signaling pathway / regulation of focal adhesion assembly / negative regulation of cell-cell adhesion / Apoptotic cleavage of cellular proteins / p130Cas linkage to MAPK signaling for integrins / positive regulation of wound healing / regulation of osteoblast differentiation / Fc-gamma receptor signaling pathway involved in phagocytosis / positive regulation of macrophage chemotaxis / regulation of cytoskeleton organization / establishment of cell polarity / vascular endothelial cell response to oscillatory fluid shear stress / GRB2:SOS provides linkage to MAPK signaling for Integrins / negative regulation of anoikis / positive regulation of epithelial cell migration / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / vascular endothelial growth factor receptor signaling pathway / RHO GTPases Activate WASPs and WAVEs / ephrin receptor signaling pathway / positive regulation of epithelial to mesenchymal transition / regulation of cell adhesion / heart morphogenesis / Integrin signaling / stress fiber / EPHB-mediated forward signaling / NCAM signaling for neurite out-growth / transforming growth factor beta receptor signaling pathway / protein tyrosine phosphatase activity / ciliary tip / SH2 domain binding / molecular function activator activity / placenta development / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / axon guidance / integrin-mediated signaling pathway / FCGR3A-mediated phagocytosis / non-specific protein-tyrosine kinase / cell motility / non-membrane spanning protein tyrosine kinase activity / Regulation of actin dynamics for phagocytic cup formation / VEGFA-VEGFR2 Pathway / integrin binding / epidermal growth factor receptor signaling pathway / regulation of cell shape / regulation of cell population proliferation / cell migration / RAF/MAP kinase cascade / actin binding / protein tyrosine kinase activity / angiogenesis / cell cortex / protein phosphatase binding / cytoskeleton / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / Extra-nuclear estrogen signaling / cilium / ciliary basal body / positive regulation of cell migration / focal adhesion / positive regulation of cell population proliferation / centrosome / protein kinase binding / negative regulation of apoptotic process / 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. / 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 / 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
Chem-10N / Focal adhesion kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsMusil, D. / Heinrich, T.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Fragment-based discovery of new highly substituted 1H-pyrrolo[2,3-b]- and 3H-imidazolo[4,5-b]-pyridines as focal adhesion kinase inhibitors.
Authors: Heinrich, T. / Seenisamy, J. / Emmanuvel, L. / Kulkarni, S.S. / Bomke, J. / Rohdich, F. / Greiner, H. / Esdar, C. / Krier, M. / Gradler, U. / Musil, D.
History
DepositionAug 29, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 4, 2013Provider: repository / Type: Initial release
Revision 1.1Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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 1.2Oct 16, 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)65,4734
Polymers64,6082
Non-polymers8652
Water6,179343
1


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


Theoretical massNumber of molelcules
Total (without water)32,7372
Polymers32,3041
Non-polymers4321
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
B: Focal adhesion kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,7372
Polymers32,3041
Non-polymers4321
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)53.378, 55.698, 192.881
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: 32304.221 Da / Num. of mol.: 2 / Fragment: Kinase domain, UNP residues 411-689
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-10N / N-(3-{[(5-cyano-2-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino]methyl}pyridin-2-yl)-N-methylmethanesulfonamide


Mass: 432.498 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H20N6O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 343 / 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: 2.22 Å3/Da / Density % sol: 44.57 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.6
Details: 0.1 M tris, 16% PEG 3350, pH 8.6, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Apr 30, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.95→48 Å / Num. obs: 42948 / % possible obs: 100 % / Observed criterion σ(I): -3 / Redundancy: 13 % / Biso Wilson estimate: 28.48 Å2 / Rmerge(I) obs: 0.089 / Net I/σ(I): 19.6
Reflection shellResolution: 1.95→2.08 Å / Redundancy: 13.3 % / Rmerge(I) obs: 0.508 / Mean I/σ(I) obs: 5.7 / Num. unique all: 7446 / % possible all: 100

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Processing

Software
NameVersionClassification
MOLREPphasing
BUSTER2.11.1refinement
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3PXK

3pxk


Resolution: 1.95→48 Å / Cor.coef. Fo:Fc: 0.9527 / Cor.coef. Fo:Fc free: 0.9443 / SU R Cruickshank DPI: 0.144 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.1944 2165 5.04 %RANDOM
Rwork0.1695 ---
obs0.1708 42947 100 %-
Displacement parametersBiso mean: 35.66 Å2
Baniso -1Baniso -2Baniso -3
1--1.8214 Å20 Å20 Å2
2--0.9291 Å20 Å2
3---0.8923 Å2
Refine analyzeLuzzati coordinate error obs: 0.217 Å
Refinement stepCycle: LAST / Resolution: 1.95→48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4254 0 62 343 4659
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014432HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.986002HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1566SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes102HARMONIC2
X-RAY DIFFRACTIONt_gen_planes638HARMONIC5
X-RAY DIFFRACTIONt_it4432HARMONIC20
X-RAY DIFFRACTIONt_omega_torsion3
X-RAY DIFFRACTIONt_other_torsion16.68
X-RAY DIFFRACTIONt_chiral_improper_torsion561SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact5454SEMIHARMONIC4
LS refinement shellResolution: 1.95→2 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2242 161 5.16 %
Rwork0.1781 2957 -
all0.1804 3118 -
obs--100 %
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)
11.04810.3354-0.06821.418-0.17570.69630.0576-0.07560.00580.0917-0.1204-0.10480.04360.09680.0628-0.0931-0.0006-0.0176-0.0308-0.0086-0.047712.2835-7.9474-38.0114
22.52250.665-0.43370.856-0.09321.9523-0.0515-0.21830.18890.05990.03030.0246-0.2191-0.11440.0211-0.02720.0325-0.0057-0.1313-0.062-0.1436-10.94912.8817-9.4802
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|414 - A|686 }A414 - 686
2X-RAY DIFFRACTION2{ B|415 - B|686 }B415 - 686

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