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- PDB-4i4f: Structure of Focal Adhesion Kinase catalytic domain in complex wi... -

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Basic information

Entry
Database: PDB / ID: 4i4f
TitleStructure of Focal Adhesion Kinase catalytic domain in complex with an allosteric binding pyrazolobenzothiazine compound.
ComponentsFocal adhesion kinase 1
Keywordstransferase/transferase inhibitor / Phosphorylated on tyrosines / localized to focal adhesions / 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 / MET activates PTK2 signaling / regulation of focal adhesion assembly / establishment of cell polarity / positive regulation of wound healing / regulation of GTPase activity / negative regulation of cell-cell adhesion / positive regulation of macrophage chemotaxis / Fc-gamma receptor signaling pathway involved in phagocytosis / p130Cas linkage to MAPK signaling for integrins / positive regulation of epithelial cell migration / regulation of cytoskeleton organization / 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 / ephrin receptor signaling pathway / positive regulation of protein kinase activity / regulation of cell adhesion / vascular endothelial growth factor receptor signaling pathway / positive regulation of epithelial to mesenchymal transition / 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 / protein tyrosine phosphatase activity / molecular function activator activity / integrin-mediated signaling pathway / cell motility / FCGR3A-mediated phagocytosis / axon guidance / non-specific protein-tyrosine kinase / regulation of protein phosphorylation / non-membrane spanning protein tyrosine kinase activity / placenta development / 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 / protein tyrosine kinase activity / angiogenesis / protein autophosphorylation / dendritic spine / Extra-nuclear estrogen signaling / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / cytoskeleton / positive regulation of cell migration / positive regulation of protein phosphorylation / intracellular membrane-bounded organelle / focal adhesion / centrosome / positive regulation of cell population proliferation / negative regulation of apoptotic process / protein kinase binding / perinuclear region of cytoplasm / ATP binding / nucleus / plasma membrane / cytoplasm / 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 / 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
Chem-1BR / ISOPROPYL ALCOHOL / Focal adhesion kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.75 Å
AuthorsSkene, R.J. / Hosfield, D.J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Structure-based discovery of cellular-active allosteric inhibitors of FAK.
Authors: Tomita, N. / Hayashi, Y. / Suzuki, S. / Oomori, Y. / Aramaki, Y. / Matsushita, Y. / Iwatani, M. / Iwata, H. / Okabe, A. / Awazu, Y. / Isono, O. / Skene, R.J. / Hosfield, D.J. / Miki, H. / ...Authors: Tomita, N. / Hayashi, Y. / Suzuki, S. / Oomori, Y. / Aramaki, Y. / Matsushita, Y. / Iwatani, M. / Iwata, H. / Okabe, A. / Awazu, Y. / Isono, O. / Skene, R.J. / Hosfield, D.J. / Miki, H. / Kawamoto, T. / Hori, A. / Baba, A.
History
DepositionNov 27, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 6, 2013Provider: repository / Type: Initial release
Revision 1.1Apr 24, 2013Group: Database references
Revision 1.2Sep 20, 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_conn / 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_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_seq_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Focal adhesion kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,5913
Polymers32,1201
Non-polymers4712
Water3,675204
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)73.087, 47.484, 83.289
Angle α, β, γ (deg.)90.00, 112.35, 90.00
Int Tables number5
Space group name H-MC121

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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: 32120.139 Da / Num. of mol.: 1 / Fragment: Kinase Domain: unp residues 411-686
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTK2, FAK, FAK1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q05397, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-IPA / ISOPROPYL ALCOHOL / 2-PROPANOL


Mass: 60.095 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O / Comment: alkaloid*YM
#3: Chemical ChemComp-1BR / N-(4-tert-butylbenzyl)-1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin-8-amine 4,4-dioxide


Mass: 410.532 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H26N4O2S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 204 / 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: 2.08 Å3/Da / Density % sol: 40.89 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 20% PEG4000, 8% 2-Propanol, 12% Glycerol, 0.1M HEPES, pH 7.5, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X6A / Wavelength: 1.1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Sep 16, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1 Å / Relative weight: 1
ReflectionResolution: 1.75→50 Å / Num. all: 26960 / Num. obs: 24123 / % possible obs: 94.2 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2
Reflection shellResolution: 1.75→1.75 Å / % possible all: 59.7

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Processing

Software
NameVersionClassification
HKL-2000data collection
MOLREPphasing
REFMAC5.7.0025refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1MP8

1mp8


Resolution: 1.75→32.21 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.937 / SU B: 6.053 / SU ML: 0.087 / Cross valid method: THROUGHOUT / ESU R: 0.132 / ESU R Free: 0.127 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22846 1284 5.1 %RANDOM
Rwork0.18612 ---
obs0.18842 24123 94.02 %-
all-26960 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 35.637 Å2
Baniso -1Baniso -2Baniso -3
1-2.54 Å20 Å21.16 Å2
2---0.4 Å20 Å2
3----1.26 Å2
Refinement stepCycle: LAST / Resolution: 1.75→32.21 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2047 0 33 204 2284
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0192129
X-RAY DIFFRACTIONr_bond_other_d0.0010.022050
X-RAY DIFFRACTIONr_angle_refined_deg1.331.9832881
X-RAY DIFFRACTIONr_angle_other_deg0.7783.0014711
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4715252
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.34323.22693
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.01615381
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.7051517
X-RAY DIFFRACTIONr_chiral_restr0.0760.2315
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212337
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02483
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.746→1.791 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.343 56 -
Rwork0.277 1099 -
obs--59.47 %
Refinement TLS params.Method: refined / Origin x: -11.0605 Å / Origin y: 0.6524 Å / Origin z: -18.3697 Å
111213212223313233
T0.0195 Å20.0062 Å2-0.02 Å2-0.0834 Å2-0.0131 Å2--0.0589 Å2
L0.8109 °20.4293 °2-0.6536 °2-2.181 °2-0.3227 °2--1.6217 °2
S-0.016 Å °0.0194 Å °-0.0084 Å °-0.1382 Å °0.0334 Å °-0.063 Å °0.0057 Å °0.0911 Å °-0.0174 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A415 - 686
2X-RAY DIFFRACTION1A701 - 1000
3X-RAY DIFFRACTION1A1001 - 1231

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