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- PDB-5ci7: Structure of ULK1 bound to a selective inhibitor -

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Basic information

Entry
Database: PDB / ID: 5ci7
TitleStructure of ULK1 bound to a selective inhibitor
ComponentsSerine/threonine-protein kinase ULK1
KeywordsTRANSFERASE/TRANSFERASE Inhibitor / inhibitor / kinase / autophagy / TRANSFERASE-TRANSFERASE Inhibitor complex
Function / homology
Function and homology information


omegasome membrane / regulation of protein lipidation / neuron projection regeneration / negative regulation of collateral sprouting / Atg1/ULK1 kinase complex / nucleophagy / positive regulation of autophagosome assembly / phagophore assembly site membrane / piecemeal microautophagy of the nucleus / RAB GEFs exchange GTP for GDP on RABs ...omegasome membrane / regulation of protein lipidation / neuron projection regeneration / negative regulation of collateral sprouting / Atg1/ULK1 kinase complex / nucleophagy / positive regulation of autophagosome assembly / phagophore assembly site membrane / piecemeal microautophagy of the nucleus / RAB GEFs exchange GTP for GDP on RABs / regulation of tumor necrosis factor-mediated signaling pathway / phagophore assembly site / axon extension / reticulophagy / TBC/RABGAPs / Macroautophagy / Receptor Mediated Mitophagy / response to starvation / autophagosome membrane / cellular response to nutrient levels / autophagosome assembly / autophagosome / regulation of macroautophagy / negative regulation of protein-containing complex assembly / positive regulation of autophagy / Regulation of TNFR1 signaling / macroautophagy / peptidyl-threonine phosphorylation / protein localization / recycling endosome / small GTPase binding / autophagy / neuron projection development / GTPase binding / peptidyl-serine phosphorylation / mitochondrial outer membrane / protein autophosphorylation / non-specific serine/threonine protein kinase / negative regulation of cell population proliferation / axon / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / protein-containing complex binding / endoplasmic reticulum membrane / signal transduction / ATP binding / identical protein binding / cytosol / cytoplasm
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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 ...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 / 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 / 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-51W / Serine/threonine-protein kinase ULK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.74 Å
AuthorsLazarus, M.B. / Shokat, K.M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI099245 United States
CitationJournal: Bioorg.Med.Chem. / Year: 2015
Title: Discovery and structure of a new inhibitor scaffold of the autophagy initiating kinase ULK1.
Authors: Lazarus, M.B. / Shokat, K.M.
History
DepositionJul 11, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 26, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 9, 2015Group: Database references
Revision 1.2Sep 27, 2017Group: Author supporting evidence / Database references / Derived calculations
Category: citation / pdbx_audit_support / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Dec 11, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Sep 27, 2023Group: 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Serine/threonine-protein kinase ULK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,0785
Polymers32,3201
Non-polymers7584
Water2,810156
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)66.860, 66.860, 116.610
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number94
Space group name H-MP42212
Components on special symmetry positions
IDModelComponents
11A-574-

HOH

21A-651-

HOH

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Components

#1: Protein Serine/threonine-protein kinase ULK1 / Autophagy-related protein 1 homolog / hATG1 / Unc-51-like kinase 1


Mass: 32320.262 Da / Num. of mol.: 1 / Fragment: kinase domain (UNP residues 1-283) / Mutation: E37A K38A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ULK1, KIAA0722 / Production host: Escherichia coli (E. coli)
References: UniProt: O75385, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-51W / N-[3-({4-[(3-aminopropyl)amino]-5-iodopyrimidin-2-yl}amino)phenyl]pyrrolidine-1-carboxamide


Mass: 481.334 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H24IN7O
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 156 / 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: 2.02 Å3/Da / Density % sol: 38.99 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5
Details: 1.55 M sodium malonate pH 7.0, 0.35 M sodium malonate pH 5.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.1 / Wavelength: 0.99997 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Mar 25, 2015
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99997 Å / Relative weight: 1
ReflectionResolution: 1.74→47.28 Å / Num. obs: 26564 / % possible obs: 96.4 % / Redundancy: 4.7 % / Net I/σ(I): 7.5

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Processing

Software
NameVersionClassification
PHENIX1.8.1_1168refinement
iMOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4WNO

4wno


Resolution: 1.74→43.813 Å / SU ML: 0.17 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 18.49 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2069 1375 5.18 %
Rwork0.1688 --
obs0.1707 26552 95.15 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.74→43.813 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2206 0 45 156 2407
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072361
X-RAY DIFFRACTIONf_angle_d1.0943184
X-RAY DIFFRACTIONf_dihedral_angle_d14.316904
X-RAY DIFFRACTIONf_chiral_restr0.062343
X-RAY DIFFRACTIONf_plane_restr0.004408
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.74-1.80220.25621170.24762392X-RAY DIFFRACTION92
1.8022-1.87430.25191340.22362516X-RAY DIFFRACTION97
1.8743-1.95970.22931560.1852507X-RAY DIFFRACTION97
1.9597-2.0630.21521340.16012550X-RAY DIFFRACTION98
2.063-2.19220.20661270.14892554X-RAY DIFFRACTION98
2.1922-2.36150.17831630.15032543X-RAY DIFFRACTION98
2.3615-2.59910.19911470.15812541X-RAY DIFFRACTION97
2.5991-2.97510.20891330.16522551X-RAY DIFFRACTION96
2.9751-3.7480.20991500.16072514X-RAY DIFFRACTION93
3.748-43.8270.19441140.17212509X-RAY DIFFRACTION87
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)
12.4331-0.829-1.02723.5659-0.63471.66120.0307-0.4328-0.22320.2814-0.1072-0.55050.08640.42020.03740.1645-0.0034-0.02020.1970.03130.1893-0.9525-49.4154-6.8656
22.22780.83180.26854.26590.81962.04750.048-0.0168-0.11810.08570.0041-0.33560.3430.3582-0.10210.13780.04510.02530.14670.01570.1146-5.375-47.124-10.0678
32.02460.21180.62711.68090.65875.4662-0.0365-0.2958-0.02330.1457-0.12060.04550.156-0.24120.06560.115100.04230.07220.01060.1205-16.1333-39.3531-6.6477
41.38691.3944-1.69151.4016-1.70322.38460.0692-0.06880.00330.0774-0.056-0.0365-0.00080.1081-0.01350.09750.01650.01840.095-0.00030.1003-10.3058-43.2292-11.7028
54.3888-1.7713-3.03632.3248-1.2715.97190.27180.48460.4513-0.0366-0.18720.1313-0.1140.7837-0.09320.07950.00350.00210.2413-0.020.1783-0.4152-26.4624-27.1174
61.4729-0.0521-1.20570.50710.20752.88820.0520.05520.0177-0.0849-0.0107-0.02750.0604-0.034-0.04590.1043-0.00170.02130.04330.0090.1065-16.9832-31.2366-22.2328
71.10360.88060.03224.06251.40790.56950.48141.32090.3174-0.9991-0.333-1.093-0.52151.09560.07210.325-0.00470.10130.56680.05560.3526-4.2383-42.6005-33.4828
81.8215-0.6355-0.96142.79162.54537.6512-0.01950.1018-0.0419-0.0796-0.08670.0530.17960.16440.13820.11690.00850.01840.04550.0090.0966-13.3607-37.3479-21.4085
91.35280.4688-1.11031.0336-0.76391.78110.1096-0.0950.08620.0556-0.1095-0.053-0.17760.06720.00460.0965-0.01630.00260.079-0.01740.0939-20.0976-22.6573-11.8413
101.5904-2.24471.78935.921-3.50282.360.3296-0.51581.011-0.21610.136-0.8958-0.7391.3409-0.3740.181-0.04770.05870.4188-0.10250.3999-7.2304-14.2955-18.3616
111.7111-1.6236-0.77144.4895-2.08783.0440.0274-0.50690.58690.877-0.37250.049-0.4848-0.0486-0.01140.331-0.10710.03620.2319-0.1220.455-12.3209-9.064-9.2282
123.10361.0699-1.25432.4485-1.12114.9462-0.022-0.06220.1319-0.0553-0.01160.09170.0051-0.24230.03530.08660.039-0.0020.08310.0340.1195-20.7265-17.8301-26.5268
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 3:24)
2X-RAY DIFFRACTION2(chain A and resid 25:49)
3X-RAY DIFFRACTION3(chain A and resid 50:75)
4X-RAY DIFFRACTION4(chain A and resid 76:103)
5X-RAY DIFFRACTION5(chain A and resid 104:108)
6X-RAY DIFFRACTION6(chain A and resid 109:147)
7X-RAY DIFFRACTION7(chain A and resid 148:157)
8X-RAY DIFFRACTION8(chain A and resid 158:166)
9X-RAY DIFFRACTION9(chain A and resid 167:217)
10X-RAY DIFFRACTION10(chain A and resid 218:223)
11X-RAY DIFFRACTION11(chain A and resid 224:237)
12X-RAY DIFFRACTION12(chain A and resid 238:279)

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