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- PDB-6yid: Crystal structure of ULK2 in complex with SBI-0206965 -

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Basic information

Entry
Database: PDB / ID: 6yid
TitleCrystal structure of ULK2 in complex with SBI-0206965
ComponentsSerine/threonine-protein kinase ULK2
KeywordsTRANSFERASE / kinase / kinase inhibitor / ULK2 / autophagy / chemical probe / Structural Genomics / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


negative regulation of collateral sprouting / collateral sprouting / phagophore assembly site membrane / piecemeal microautophagy of the nucleus / axon extension / phagophore assembly site / reticulophagy / response to starvation / autophagosome assembly / autophagosome ...negative regulation of collateral sprouting / collateral sprouting / phagophore assembly site membrane / piecemeal microautophagy of the nucleus / axon extension / phagophore assembly site / reticulophagy / response to starvation / autophagosome assembly / autophagosome / positive regulation of autophagy / cytoplasmic vesicle membrane / autophagy / protein autophosphorylation / non-specific serine/threonine protein kinase / protein serine kinase activity / protein serine/threonine kinase activity / signal transduction / ATP binding / cytoplasm / cytosol
Similarity search - Function
Serine/threonine-protein kinase, Ulk1/Ulk2 / : / ATG1-like, MIT domain 2 / Serine/threonine-protein kinase Atg1-like, tMIT domain / Atg1-like, MIT domain 1 / Serine/threonine-protein kinase Atg1-like / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. ...Serine/threonine-protein kinase, Ulk1/Ulk2 / : / ATG1-like, MIT domain 2 / Serine/threonine-protein kinase Atg1-like, tMIT domain / Atg1-like, MIT domain 1 / Serine/threonine-protein kinase Atg1-like / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-EDJ / Serine/threonine-protein kinase ULK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsChaikuad, A. / Ren, H. / Bakas, N.A. / Lambert, L.J. / Cosford, N.D.P. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: J.Med.Chem. / Year: 2020
Title: Design, Synthesis, and Characterization of an Orally Active Dual-Specific ULK1/2 Autophagy Inhibitor that Synergizes with the PARP Inhibitor Olaparib for the Treatment of Triple-Negative Breast Cancer.
Authors: Ren, H. / Bakas, N.A. / Vamos, M. / Chaikuad, A. / Limpert, A.S. / Wimer, C.D. / Brun, S.N. / Lambert, L.J. / Tautz, L. / Celeridad, M. / Sheffler, D.J. / Knapp, S. / Shaw, R.J. / Cosford, N.D.P.
History
DepositionApr 1, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 17, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 13, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jan 24, 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: Serine/threonine-protein kinase ULK2
B: Serine/threonine-protein kinase ULK2
C: Serine/threonine-protein kinase ULK2
D: Serine/threonine-protein kinase ULK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)129,0288
Polymers127,0714
Non-polymers1,9574
Water88349
1
A: Serine/threonine-protein kinase ULK2
B: Serine/threonine-protein kinase ULK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,5144
Polymers63,5352
Non-polymers9792
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4330 Å2
ΔGint-27 kcal/mol
Surface area25280 Å2
MethodPISA
2
C: Serine/threonine-protein kinase ULK2
hetero molecules

D: Serine/threonine-protein kinase ULK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,5144
Polymers63,5352
Non-polymers9792
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_565x,y+1,z1
Buried area4360 Å2
ΔGint-28 kcal/mol
Surface area25390 Å2
MethodPISA
Unit cell
Length a, b, c (Å)75.968, 76.526, 95.244
Angle α, β, γ (deg.)90.000, 97.030, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

Component-ID: _ / Refine code: _

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11SERSERGLUGLUAA0 - 2724 - 276
21SERSERGLUGLUBB0 - 2724 - 276
12SERSERLEULEUAA0 - 2714 - 275
22SERSERLEULEUCC0 - 2714 - 275
13SERSERGLYGLYAA0 - 2744 - 278
23SERSERGLYGLYDD0 - 2744 - 278
14GLYGLYGLUGLUBB-2 - 2722 - 276
24GLYGLYGLUGLUCC-2 - 2722 - 276
15SERSERGLNGLNBB0 - 2734 - 277
25SERSERGLNGLNDD0 - 2734 - 277
16SERSERLEULEUCC0 - 2714 - 275
26SERSERLEULEUDD0 - 2714 - 275

NCS ensembles :
ID
1
2
3
4
5
6

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Components

#1: Protein
Serine/threonine-protein kinase ULK2 / Unc-51-like kinase 2


Mass: 31767.721 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ULK2, KIAA0623 / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): -R3-pRARE2
References: UniProt: Q8IYT8, non-specific serine/threonine protein kinase
#2: Chemical
ChemComp-EDJ / 2-({5-bromo-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}oxy)-N-methylbenzene-1-carboximidic acid


Mass: 489.319 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H21BrN4O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 49 / Source method: isolated from a natural source / Formula: H2O
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: 2.16 Å3/Da / Density % sol: 43.12 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / pH: 5.75
Details: 32.5% PEG 3350, 0.1M sodium citrate, pH 5.9, 0.2M MgCl2, 0.1M bis-tris, pH 5.75

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.99986 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Apr 19, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99986 Å / Relative weight: 1
ReflectionResolution: 2.7→48.55 Å / Num. obs: 29707 / % possible obs: 99.2 % / Redundancy: 6.1 % / CC1/2: 0.999 / Rmerge(I) obs: 0.075 / Rpim(I) all: 0.036 / Rrim(I) all: 0.088 / Net I/σ(I): 13.6
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2.7-2.856.30.82743140.740.3910.99499.7
8.54-48.555.60.0329630.9990.0150.03597

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Processing

Software
NameVersionClassification
Aimless0.7.1data scaling
REFMAC5.8.0222refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6QAV

6qav


Resolution: 2.7→48.55 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.941 / SU B: 31.49 / SU ML: 0.306 / SU R Cruickshank DPI: 0.2933 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.359
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2379 1415 4.8 %RANDOM
Rwork0.1921 ---
obs0.1943 28278 99.01 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 174.39 Å2 / Biso mean: 77.216 Å2 / Biso min: 35.25 Å2
Baniso -1Baniso -2Baniso -3
1-0.84 Å2-0 Å2-0.06 Å2
2--2.32 Å20 Å2
3----3.05 Å2
Refinement stepCycle: final / Resolution: 2.7→48.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8293 0 124 49 8466
Biso mean--65.1 56.53 -
Num. residues----1039
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0148624
X-RAY DIFFRACTIONr_bond_other_d0.0010.0177848
X-RAY DIFFRACTIONr_angle_refined_deg0.9841.64411632
X-RAY DIFFRACTIONr_angle_other_deg0.7811.64518326
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7451033
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.72322.217451
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.835151517
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.4641553
X-RAY DIFFRACTIONr_chiral_restr0.0510.21076
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0210040
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021628
Refine LS restraints NCS

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

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A77940.06
12B77940.06
21A79330.06
22C79330.06
31A79450.06
32D79450.06
41B78460.07
42C78460.07
51B78130.07
52D78130.07
61C79210.05
62D79210.05
LS refinement shellResolution: 2.7→2.77 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.351 102 -
Rwork0.299 2075 -
all-2177 -
obs--99.54 %
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)
10.4134-0.25740.23680.47360.33131.1325-0.0112-0.0043-0.01650.144-0.0008-0.02820.1328-0.0520.0120.1962-0.0267-0.03420.03290.01480.09060.6816-1.259525.7115
20.4527-0.1141-0.22930.4090.15921.6273-0.0160.077-0.00610.1133-0.03960.0192-0.1081-0.12430.05560.19710.0022-0.00960.02590.01930.0895-10.292128.826111.3831
30.4431-0.6262-0.28041.15710.68190.5014-0.1348-0.07920.01610.20810.11070.00870.01690.04950.02410.37030.0404-0.02610.0361-0.02460.0256-5.218832.152634.7254
40.86410.61150.98570.90210.49371.2380.04520.0434-0.126-0.02650.1807-0.03420.09170.0207-0.22590.04110.0013-0.03050.2214-0.06610.134928.556233.352721.5962
51.079-0.59230.16064.0402-0.5141.52130.0320.0951-0.09570.41060.1858-0.0345-0.0950.1164-0.21780.1363-0.0036-0.0480.218-0.05990.073438.524535.121443.0513
60.2713-0.1526-0.01510.0884-0.01031.50520.00260.02560.07220.0047-0.023-0.05590.05370.0660.02040.0872-0.0905-0.00330.1403-0.05490.171835.5057-15.300911.6139
71.94980.34061.00482.0120.7372.60140.0587-0.77470.23830.1186-0.0112-0.1412-0.0165-0.2275-0.04750.1094-0.0664-0.01420.3695-0.14870.125543.7371-6.036731.7227
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A0 - 274
2X-RAY DIFFRACTION2B-3 - 165
3X-RAY DIFFRACTION3B166 - 273
4X-RAY DIFFRACTION4C-2 - 187
5X-RAY DIFFRACTION5C188 - 272
6X-RAY DIFFRACTION6D0 - 187
7X-RAY DIFFRACTION7D188 - 274

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