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- PDB-8sv9: Crystal structure of ULK1 kinase domain with inhibitor MR-2088 -

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Basic information

Entry
Database: PDB / ID: 8sv9
TitleCrystal structure of ULK1 kinase domain with inhibitor MR-2088
ComponentsSerine/threonine-protein kinase ULK1
KeywordsTRANSFERASE/INHIBITOR / Autophagy / Inhibitor / Complex / Kinase / 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 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain ...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 / 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
Similarity search - Domain/homology
: / Serine/threonine-protein kinase ULK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsSchonbrunn, E. / Sun, L.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Eur.J.Med.Chem. / Year: 2024
Title: Development of potent and selective ULK1/2 inhibitors based on 7-azaindole scaffold with favorable in vivo properties.
Authors: Morozova, A. / Chan, S.C. / Bayle, S. / Sun, L. / Grassie, D. / Iermolaieva, A. / Kalaga, M.N. / Frydman, S. / Sansil, S. / Schonbrunn, E. / Duckett, D. / Monastyrskyi, A.
History
DepositionMay 15, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 27, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)65,73511
Polymers64,2842
Non-polymers1,4519
Water2,306128
1
A: Serine/threonine-protein kinase ULK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,8375
Polymers32,1421
Non-polymers6954
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Serine/threonine-protein kinase ULK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,8996
Polymers32,1421
Non-polymers7575
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)112.060, 139.960, 87.450
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number21
Space group name H-MC222
Components on special symmetry positions
IDModelComponents
11A-303-

SO4

21B-304-

SO4

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Components

#1: Protein Serine/threonine-protein kinase ULK1 / Autophagy-related protein 1 homolog / ATG1 / hATG1 / Unc-51-like kinase 1


Mass: 32142.006 Da / Num. of mol.: 2 / Fragment: kinase domain / Mutation: E37A, K38A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ULK1, KIAA0722 / Plasmid: pET28a / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: O75385, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-WXH / (4P)-4-[(2P)-2-(1,2,5,6-tetrahydropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-(2,2,2-trifluoroethyl)thiophene-2-carboxamide


Mass: 406.425 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H17F3N4OS / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 128 / 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: 2.68 Å3/Da / Density % sol: 54.11 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 0.05 M Bis-Tris pH 5.5, 0.2 M (NH4)2SO4, 20% PEG3350

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54178 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: May 9, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 2.3→47.18 Å / Num. obs: 29836 / % possible obs: 96.5 % / Redundancy: 7.1 % / CC1/2: 0.999 / Rrim(I) all: 0.101 / Net I/σ(I): 17.8
Reflection shellResolution: 2.3→2.36 Å / Redundancy: 4.4 % / Mean I/σ(I) obs: 1.7 / Num. unique obs: 1981 / CC1/2: 0.574 / Rrim(I) all: 0.94 / % possible all: 87

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSVERSION Jan 10, 2022data reduction
XSCALEVERSION Jan 10, 2022data scaling
PHENIX1.20.1_4487phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→47.18 Å / SU ML: 0.31 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 27.45 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2469 1791 6 %
Rwork0.2099 --
obs0.2122 29836 96.49 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.3→47.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4352 0 90 128 4570
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.002
X-RAY DIFFRACTIONf_angle_d0.551
X-RAY DIFFRACTIONf_dihedral_angle_d10.558651
X-RAY DIFFRACTIONf_chiral_restr0.041675
X-RAY DIFFRACTIONf_plane_restr0.004800
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.360.32761240.29831934X-RAY DIFFRACTION87
2.36-2.430.31091330.27462090X-RAY DIFFRACTION96
2.43-2.510.33151340.27212100X-RAY DIFFRACTION96
2.51-2.60.33871370.24662135X-RAY DIFFRACTION97
2.6-2.70.29591360.24832142X-RAY DIFFRACTION97
2.7-2.830.33811370.26772134X-RAY DIFFRACTION97
2.83-2.980.30741380.25772172X-RAY DIFFRACTION97
2.98-3.160.29311380.24862155X-RAY DIFFRACTION97
3.16-3.410.24641390.22582183X-RAY DIFFRACTION98
3.41-3.750.22871400.22200X-RAY DIFFRACTION98
3.75-4.290.20761420.17342221X-RAY DIFFRACTION98
4.29-5.40.19141430.15642237X-RAY DIFFRACTION99
5.41-47.180.21471500.19052342X-RAY DIFFRACTION98
Refinement TLS params.Method: refined / Origin x: -29.9948 Å / Origin y: 0.0012 Å / Origin z: 19.9524 Å
111213212223313233
T0.2776 Å2-0.041 Å2-0.0062 Å2-0.2612 Å20.0138 Å2--0.2174 Å2
L1.4844 °2-0.3936 °2-1.1399 °2-0.5421 °20.2225 °2--0.904 °2
S-0.0057 Å °0.0118 Å °0.0703 Å °-0.0451 Å °0.0404 Å °0.0058 Å °0.0279 Å °-0.0788 Å °-0.0318 Å °
Refinement TLS groupSelection details: all

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