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- PDB-7pi4: FAK Protac GSK215 in complex with FAK and pVHL:ElonginC:ElonginB -

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Basic information

Entry
Database: PDB / ID: 7pi4
TitleFAK Protac GSK215 in complex with FAK and pVHL:ElonginC:ElonginB
Components
  • Elongin-B
  • Focal adhesion kinase 1
  • Isoform 2 of Elongin-C
  • von Hippel-Lindau disease tumor suppressor
KeywordsTRANSFERASE / PROTAC
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 / regulation of cellular response to hypoxia / detection of muscle stretch / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / JUN kinase binding / target-directed miRNA degradation ...netrin-activated signaling pathway / regulation of substrate adhesion-dependent cell spreading / regulation of endothelial cell migration / regulation of epithelial cell migration / regulation of cellular response to hypoxia / detection of muscle stretch / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / JUN kinase binding / target-directed miRNA degradation / transcription elongation factor activity / VCB complex / elongin complex / 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 / Replication of the SARS-CoV-1 genome / Signal regulatory protein family interactions / Cul5-RING ubiquitin ligase complex / regulation of GTPase activity / growth hormone receptor signaling pathway / MET activates PTK2 signaling / regulation of focal adhesion assembly / intracellular membraneless organelle / Cul2-RING ubiquitin ligase complex / negative regulation of cell-cell adhesion / positive regulation of wound healing / p130Cas linkage to MAPK signaling for integrins / regulation of osteoblast differentiation / SUMOylation of ubiquitinylation proteins / 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 / negative regulation of transcription elongation by RNA polymerase II / GRB2:SOS provides linkage to MAPK signaling for Integrins / regulation of protein phosphorylation / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / negative regulation of anoikis / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / 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 / Tat-mediated elongation of the HIV-1 transcript / vascular endothelial growth factor receptor signaling pathway / ubiquitin-like ligase-substrate adaptor activity / Formation of HIV-1 elongation complex containing HIV-1 Tat / negative regulation of signal transduction / regulation of cell adhesion / Formation of HIV elongation complex in the absence of HIV Tat / positive regulation of epithelial to mesenchymal transition / heart morphogenesis / RNA Polymerase II Transcription Elongation / stress fiber / Formation of RNA Pol II elongation complex / negative regulation of TORC1 signaling / protein serine/threonine kinase binding / RNA Polymerase II Pre-transcription Events / EPHB-mediated forward signaling / Integrin signaling / protein tyrosine phosphatase activity / NCAM signaling for neurite out-growth / transforming growth factor beta receptor signaling pathway / negative regulation of autophagy / SH2 domain binding / axon guidance / molecular function activator activity / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / transcription corepressor binding / integrin-mediated signaling pathway / positive regulation of cell differentiation / non-membrane spanning protein tyrosine kinase activity / TP53 Regulates Transcription of DNA Repair Genes / FCGR3A-mediated phagocytosis / transcription initiation at RNA polymerase II promoter / non-specific protein-tyrosine kinase / cell motility / placenta development / transcription elongation by RNA polymerase II / Vif-mediated degradation of APOBEC3G / Inactivation of CSF3 (G-CSF) signaling / cell morphogenesis / peptidyl-tyrosine phosphorylation / Evasion by RSV of host interferon responses / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Regulation of actin dynamics for phagocytic cup formation / VEGFA-VEGFR2 Pathway / epidermal growth factor receptor signaling pathway / Regulation of expression of SLITs and ROBOs / ubiquitin-protein transferase activity / transcription corepressor activity
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 / von Hippel-Lindau disease tumour suppressor, beta/alpha domain / von Hippel-Lindau disease tumour suppressor, alpha 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 / von Hippel-Lindau disease tumour suppressor, beta/alpha domain / von Hippel-Lindau disease tumour suppressor, alpha domain / von Hippel-Lindau disease tumour suppressor, beta domain / VHL superfamily / von Hippel-Lindau disease tumour suppressor, alpha domain superfamily / von Hippel-Lindau disease tumour suppressor, beta domain superfamily / VHL beta domain / VHL box domain / Elongin B / 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 / Ubiquitin family / Ubiquitin homologues / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Ubiquitin domain profile. / Ubiquitin-like domain / 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 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-7QB / DI(HYDROXYETHYL)ETHER / von Hippel-Lindau disease tumor suppressor / Focal adhesion kinase 1 / Isoform 2 of Elongin-C / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.24 Å
AuthorsChung, C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Angew.Chem.Int.Ed.Engl. / Year: 2021
Title: Discovery and Characterisation of Highly Cooperative FAK-Degrading PROTACs.
Authors: Law, R.P. / Nunes, J. / Chung, C.W. / Bantscheff, M. / Buda, K. / Dai, H. / Evans, J.P. / Flinders, A. / Klimaszewska, D. / Lewis, A.J. / Muelbaier, M. / Scott-Stevens, P. / Stacey, P. / ...Authors: Law, R.P. / Nunes, J. / Chung, C.W. / Bantscheff, M. / Buda, K. / Dai, H. / Evans, J.P. / Flinders, A. / Klimaszewska, D. / Lewis, A.J. / Muelbaier, M. / Scott-Stevens, P. / Stacey, P. / Tame, C.J. / Watt, G.F. / Zinn, N. / Queisser, M.A. / Harling, J.D. / Benowitz, A.B.
History
DepositionAug 19, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 29, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 20, 2021Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jan 31, 2024Group: Data collection / Derived calculations / Refinement description
Category: atom_type / chem_comp_atom ...atom_type / chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Item: _atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
AAA: von Hippel-Lindau disease tumor suppressor
BBB: Elongin-B
CCC: Isoform 2 of Elongin-C
DDD: Focal adhesion kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,40424
Polymers72,0864
Non-polymers2,31920
Water2,702150
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10680 Å2
ΔGint8 kcal/mol
Surface area29820 Å2
Unit cell
Length a, b, c (Å)59.550, 77.260, 175.180
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 4 types, 4 molecules AAABBBCCCDDD

#1: Protein von Hippel-Lindau disease tumor suppressor / Protein G7 / pVHL


Mass: 18012.527 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: VHL / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P40337
#2: Protein Elongin-B / EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / ...EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / Transcription elongation factor B polypeptide 2


Mass: 11845.521 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOB, TCEB2 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q15370
#3: Protein Isoform 2 of Elongin-C / EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / ...EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / Transcription elongation factor B polypeptide 1


Mass: 10843.420 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOC, TCEB1 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q15369-2
#4: 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: 31384.350 Da / Num. of mol.: 1
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

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Non-polymers , 5 types, 170 molecules

#5: Chemical ChemComp-7QB / (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(3-methoxy-4-((4-((2-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide / (2S,4R)-1-[(2S)-2-[2-[4-[3-methoxy-4-[[4-[[2-(methylcarbamoyl)phenyl]amino]-5-(trifluoromethyl)pyridin-2-yl]amino]phenyl]piperazin-1-yl]ethanoylamino]-3,3-dimethyl-butanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-4-oxidanyl-pyrrolidine-2-carboxamide


Mass: 985.127 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C50H59F3N10O6S / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C4H10O3
#7: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: C2H6O2
#8: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 150 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2.87 Å3/Da / Density % sol: 57.1 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: 0.05M CaCl, 0.1M MES pH 6.5, 45%v/v, PEG200

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Jun 11, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.24→58.39 Å / Num. obs: 39778 / % possible obs: 99.9 % / Redundancy: 6.7 % / CC1/2: 0.984 / Rmerge(I) obs: 0.198 / Net I/σ(I): 6.2
Reflection shellResolution: 2.24→2.3 Å / Redundancy: 6.9 % / Rmerge(I) obs: 0.978 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 2918 / CC1/2: 0.779 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0257refinement
xia2data reduction
Aimlessdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3PSK

3psk


Resolution: 2.24→56.381 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.922 / SU B: 6.949 / SU ML: 0.17 / Cross valid method: FREE R-VALUE / ESU R: 0.249 / ESU R Free: 0.213
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2512 1963 4.943 %
Rwork0.1953 37753 -
all0.198 --
obs-39716 99.882 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL PLUS MASK
Displacement parametersBiso mean: 53.214 Å2
Baniso -1Baniso -2Baniso -3
1--0.015 Å20 Å20 Å2
2--0.763 Å2-0 Å2
3----0.748 Å2
Refinement stepCycle: LAST / Resolution: 2.24→56.381 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4929 0 155 150 5234
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0135190
X-RAY DIFFRACTIONr_bond_other_d0.0010.0174914
X-RAY DIFFRACTIONr_angle_refined_deg1.4311.6546997
X-RAY DIFFRACTIONr_angle_other_deg1.1941.58811390
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.0785609
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.38921.143280
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.96115890
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.4151545
X-RAY DIFFRACTIONr_chiral_restr0.0620.2658
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.025822
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021097
X-RAY DIFFRACTIONr_nbd_refined0.1940.2959
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1860.24515
X-RAY DIFFRACTIONr_nbtor_refined0.1640.22431
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0860.22356
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1670.2171
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.1250.21
X-RAY DIFFRACTIONr_metal_ion_refined0.1280.22
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1740.210
X-RAY DIFFRACTIONr_nbd_other0.1940.253
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1190.29
X-RAY DIFFRACTIONr_mcbond_it5.867.042452
X-RAY DIFFRACTIONr_mcbond_other5.8597.0382450
X-RAY DIFFRACTIONr_mcangle_it8.13315.793056
X-RAY DIFFRACTIONr_mcangle_other8.13315.7953056
X-RAY DIFFRACTIONr_scbond_it7.0797.972738
X-RAY DIFFRACTIONr_scbond_other7.0777.9712739
X-RAY DIFFRACTIONr_scangle_it10.18117.3183941
X-RAY DIFFRACTIONr_scangle_other10.17917.323942
X-RAY DIFFRACTIONr_lrange_it12.04962.5465491
X-RAY DIFFRACTIONr_lrange_other12.05762.5325475
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
2.24-2.2980.3241490.26227590.26529110.7980.80799.89690.242
2.298-2.3610.2611320.23226710.23328080.8690.86899.82190.215
2.361-2.4290.2971440.23225800.23527310.8420.8799.74370.212
2.429-2.5040.2411280.21525650.21626970.8990.999.85170.191
2.504-2.5860.31150.20624600.2125750.8670.9071000.189
2.586-2.6760.2531120.19823830.224950.9060.9211000.184
2.676-2.7770.2811080.20223190.20624270.9040.9161000.188
2.777-2.890.231090.19422170.19523260.9130.931000.184
2.89-3.0180.291250.18921100.19522350.8990.9361000.182
3.018-3.1650.2711090.18920400.19321510.9080.9399.9070.19
3.165-3.3360.2381050.19419560.19620610.9240.9321000.194
3.336-3.5380.261920.19518390.19819440.920.93599.33130.205
3.538-3.7810.2191000.1817240.18218250.940.94799.94520.195
3.781-4.0820.266850.17316410.17817260.9230.951000.196
4.082-4.4690.211750.15815020.16115770.9450.961000.188
4.469-4.9930.247690.17113820.17414510.940.9541000.21
4.993-5.7580.233780.20412040.20612830.9430.95399.92210.244
5.758-7.0340.249570.20310490.20511120.9360.94699.46040.248
7.034-9.8710.201470.1758400.1778870.9610.9691000.216
9.871-56.3810.312240.3015120.3025380.920.93399.62830.385

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