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- PDB-4y8d: Crystal structure of Cyclin-G associated kinase (GAK) complexed w... -

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Basic information

Entry
Database: PDB / ID: 4y8d
TitleCrystal structure of Cyclin-G associated kinase (GAK) complexed with selective 12i inhibitor
Components
  • Cyclin-G-associated kinaseGAK (protein)
  • nanobodySingle-domain antibody
KeywordsTRANSFERASE / kinase / nanobody / inhibitor / Structural Genomics / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


regulation of clathrin coat assembly / synaptic vesicle uncoating / Golgi to lysosome transport / protein localization to Golgi apparatus / clathrin coat assembly / clathrin coat disassembly / clathrin-dependent endocytosis / endoplasmic reticulum organization / clathrin-coated vesicle / clathrin binding ...regulation of clathrin coat assembly / synaptic vesicle uncoating / Golgi to lysosome transport / protein localization to Golgi apparatus / clathrin coat assembly / clathrin coat disassembly / clathrin-dependent endocytosis / endoplasmic reticulum organization / clathrin-coated vesicle / clathrin binding / Golgi Associated Vesicle Biogenesis / Golgi organization / chaperone cofactor-dependent protein refolding / intracellular transport / receptor-mediated endocytosis / cyclin binding / protein localization to plasma membrane / negative regulation of neuron projection development / presynapse / Clathrin-mediated endocytosis / protein-folding chaperone binding / vesicle / non-specific serine/threonine protein kinase / cell cycle / phosphorylation / focal adhesion / protein serine kinase activity / intracellular membrane-bounded organelle / protein serine/threonine kinase activity / perinuclear region of cytoplasm / Golgi apparatus / ATP binding / membrane / cytosol / cytoplasm
Similarity search - Function
Tensin phosphatase, C2 domain / Tensin-type phosphatase domain / C2 domain of PTEN tumour-suppressor protein / Phosphatase tensin-type domain profile. / C2 tensin-type domain profile. / C2 domain of PTEN tumour-suppressor protein / DnaJ molecular chaperone homology domain / dnaJ domain profile. / Chaperone J-domain superfamily / DnaJ domain ...Tensin phosphatase, C2 domain / Tensin-type phosphatase domain / C2 domain of PTEN tumour-suppressor protein / Phosphatase tensin-type domain profile. / C2 tensin-type domain profile. / C2 domain of PTEN tumour-suppressor protein / DnaJ molecular chaperone homology domain / dnaJ domain profile. / Chaperone J-domain superfamily / DnaJ domain / C2 domain superfamily / Protein-tyrosine phosphatase-like / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Immunoglobulins / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / Immunoglobulin-like / Sandwich / 2-Layer Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-49J / Cyclin-G-associated kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
Lama glama (llama)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsChaikuad, A. / Heroven, C. / Nowak, R. / De Jonghe, S. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: J.Med.Chem. / Year: 2015
Title: Selective Inhibitors of Cyclin G Associated Kinase (GAK) as Anti-Hepatitis C Agents.
Authors: Kovackova, S. / Chang, L. / Bekerman, E. / Neveu, G. / Barouch-Bentov, R. / Chaikuad, A. / Heroven, C. / Sala, M. / De Jonghe, S. / Knapp, S. / Einav, S. / Herdewijn, P.
History
DepositionFeb 16, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Apr 8, 2015Provider: repository / Type: Initial release
Revision 1.1Apr 22, 2015Group: Database references
Revision 1.2May 6, 2015Group: Database references
Revision 1.3Jan 10, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cyclin-G-associated kinase
C: nanobody
B: Cyclin-G-associated kinase
D: nanobody
hetero molecules


Theoretical massNumber of molelcules
Total (without water)107,53311
Polymers106,5384
Non-polymers9957
Water7,098394
1
A: Cyclin-G-associated kinase
C: nanobody
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,7365
Polymers53,2692
Non-polymers4673
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Cyclin-G-associated kinase
D: nanobody
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,7986
Polymers53,2692
Non-polymers5294
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)37.706, 68.703, 89.868
Angle α, β, γ (deg.)109.70, 95.08, 99.04
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12C
22D

NCS domain segments:

Component-ID: 0 / Refine code: 0

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11ASPASPGLUGLUAA27 - 33316 - 322
21ASPASPGLUGLUBC27 - 33316 - 322
12GLNGLNVALVALCB1 - 1191 - 119
22GLNGLNVALVALDD1 - 1191 - 119

NCS ensembles :
ID
1
2

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Components

#1: Protein Cyclin-G-associated kinase / GAK (protein)


Mass: 38183.551 Da / Num. of mol.: 2 / Fragment: UNP residues 14-351
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GAK / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): R3 pRARE2
References: UniProt: O14976, non-specific serine/threonine protein kinase
#2: Protein nanobody / Single-domain antibody


Mass: 15085.511 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Lama glama (llama)
#3: Chemical ChemComp-49J / 2-methoxy-4-[3-(morpholin-4-yl)[1,2]thiazolo[4,3-b]pyridin-6-yl]aniline


Mass: 342.415 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H18N4O2S
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 394 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.01 Å3/Da / Density % sol: 38.75 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / pH: 6.2
Details: 9% Broad-molecular weight PEG Smears (BMW PEG smears), 0.1M MES pH 6.2, 0.15M calcium chloride

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.92 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Oct 31, 2013
RadiationMonochromator: Si (111) double crystal monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 2.1→43.58 Å / Num. obs: 45797 / % possible obs: 94.7 % / Redundancy: 3.7 % / Rmerge(I) obs: 0.071 / Net I/σ(I): 11.9
Reflection shellResolution: 2.1→2.21 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.602 / Mean I/σ(I) obs: 2 / % possible all: 92.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
XDSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4C58

4c58


Resolution: 2.1→43.58 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.922 / SU B: 12.053 / SU ML: 0.157 / Cross valid method: THROUGHOUT / ESU R: 0.252 / ESU R Free: 0.194 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23154 2310 5 %RANDOM
Rwork0.19234 ---
obs0.19432 43487 94.74 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 70.498 Å2
Baniso -1Baniso -2Baniso -3
1-2.6 Å20.31 Å2-0.64 Å2
2--0.5 Å2-0.55 Å2
3----1.93 Å2
Refine analyzeLuzzati coordinate error obs: 0.342 Å
Refinement stepCycle: 1 / Resolution: 2.1→43.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5909 0 68 394 6371
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0196164
X-RAY DIFFRACTIONr_bond_other_d0.0040.025891
X-RAY DIFFRACTIONr_angle_refined_deg1.4361.9688339
X-RAY DIFFRACTIONr_angle_other_deg0.893.00313511
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8535779
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.14123.714280
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.354151055
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.6351549
X-RAY DIFFRACTIONr_chiral_restr0.080.2934
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.027031
X-RAY DIFFRACTIONr_gen_planes_other0.0030.021456
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_it1.3051.7783074
X-RAY DIFFRACTIONr_mcbond_other1.3051.7783073
X-RAY DIFFRACTIONr_mcangle_it2.2312.653834
X-RAY DIFFRACTIONr_mcangle_other2.2312.653835
X-RAY DIFFRACTIONr_scbond_it1.6452.033090
X-RAY DIFFRACTIONr_scbond_other1.6422.033090
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.6172.9614495
X-RAY DIFFRACTIONr_long_range_B_refined7.2615.5116983
X-RAY DIFFRACTIONr_long_range_B_other7.25915.5166984
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A164180.03
12B164180.03
21C65860.04
22D65860.04
LS refinement shellResolution: 2.1→2.155 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.332 163 -
Rwork0.279 3132 -
obs--93.63 %
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)
10.8571-0.00610.60093.0363-0.74954.1270.1485-0.0389-0.4099-0.22540.00290.13091.3716-0.272-0.15140.7410.0469-0.02820.37-0.17710.422231.919747.2778-70.9393
21.3163-0.84380.09842.29850.56763.7512-0.0322-0.0774-0.15890.0650.02440.2340.619-0.10420.00780.18020.01610.01460.1841-0.13660.167528.491365.3621-53.2098
39.97020.1680.48695.13541.57634.71250.0091-1.0710.4913-0.22410.0753-0.1394-0.98090.0719-0.08440.7880.06670.00260.3936-0.08050.548830.310297.3901-85.4437
41.07590.35030.29011.71391.09853.6705-0.0639-0.00910.2144-0.06610.00280.1565-0.7277-0.04910.06120.2360.0724-0.04080.1431-0.11550.193429.137974.8334-95.6231
53.06610.86581.26322.26421.03812.8085-0.15570.26680.2612-0.01210.0529-0.1875-0.07990.23620.10270.02680.0129-0.02690.187-0.11580.225440.638891.3684-46.6586
63.0341-0.5752-0.8322.01120.58212.902-0.0944-0.1966-0.4079-0.05460.003-0.20880.01110.18230.09140.0160.0398-0.00870.1642-0.1230.272940.664544.7959-107.1691
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A27 - 118
2X-RAY DIFFRACTION2A119 - 333
3X-RAY DIFFRACTION3B27 - 49
4X-RAY DIFFRACTION4B50 - 333
5X-RAY DIFFRACTION5C1 - 120
6X-RAY DIFFRACTION6D1 - 121

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