PDB-8p5k: Kinase domain of mutant human ULK1 in complex with compound MRT68921

ID or keywords:

Entry

Database: PDB / ID: 8p5k

Title

Kinase domain of mutant human ULK1 in complex with compound MRT68921

Components

Serine/threonine-protein kinase ULK1

Keywords

TRANSFERASE / Autophagy / Unc-like 1 kinase

Function / homology

Function and homology information

neuron projection regeneration / omegasome membrane / negative regulation of collateral sprouting / Atg1/ULK1 kinase complex / 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 ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 2.209 Å

Authors

Battista, T. / Semrau, M.S. / Heroux, A. / Lolli, G. / Storici, P.

Funding support

1items

Citation

Journal: To Be Published
Title: Crystal structures of ULK1 in complex with KCGS compounds
Authors: Battista, T. / Semrau, M.S. / Heroux, A. / Lolli, G. / Storici, P.

History

Deposition	May 24, 2023	Deposition site: PDBE / Processing site: PDBE
Revision 1.0	Jun 5, 2024	Provider: repository / Type: Initial release
Revision 1.1	Oct 16, 2024	Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

Structure viewer	Molecule: MolmilJmol/JSmol

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PDBx/mmCIF format	8p5k.cif.gz	458.8 KB	Display	PDBx/mmCIF format
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Validation report

Summary document	8p5k_validation.pdf.gz	1.7 MB	Display	wwPDB validaton report
Full document	8p5k_full_validation.pdf.gz	1.7 MB	Display
Data in XML	8p5k_validation.xml.gz	47.2 KB	Display
Data in CIF	8p5k_validation.cif.gz	66.9 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/p5/8p5k ftp://data.pdbj.org/pub/pdb/validation_reports/p5/8p5k	HTTPS FTP

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Related structure data

Related structure data	8p5gC 8p5hC 8p5iC 8p5jC 8p5lC C: citing same article (ref.)
Similar structure data	Similarity search - Function & homologyF&H Search Similarity search - FunctionF&H Search Similarity search - HomologyF&H Search

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Links

PDB pages	PDBj / wwPDB / NCBI
Related items in Molecule of the Month	#203 - Nov 2016 Aminopeptidase 1 and Autophagy similarity (1) #252 - Dec 2020 Hepatitis C Virus Protease/Helicase similarity (1) #60 - Dec 2004 Ubiquitin similarity (2) #115 - Jul 2009 beta-Secretase similarity (1) #141 - Sep 2011 O-GlcNAc Transferase similarity (1) #43 - Jul 2003 Src Tyrosine Kinase similarity (1) #234 - Jun 2019 MDM2 and Cancer similarity (1) #56 - Aug 2004 Caspases similarity (1)

PDB pages

PDBj /

wwPDB /

NCBI

Related items in Molecule of the Month

#203 - Nov 2016
Aminopeptidase 1 and Autophagy
similarity (1)
#252 - Dec 2020
Hepatitis C Virus Protease/Helicase
similarity (1)
#60 - Dec 2004
Ubiquitin
similarity (2)
#115 - Jul 2009
beta-Secretase
similarity (1)
#141 - Sep 2011
O-GlcNAc Transferase
similarity (1)
#43 - Jul 2003
Src Tyrosine Kinase
similarity (1)
#234 - Jun 2019
MDM2 and Cancer
similarity (1)
#56 - Aug 2004
Caspases
similarity (1)

Deposited unit

A: Serine/threonine-protein kinase ULK1

B: Serine/threonine-protein kinase ULK1

C: Serine/threonine-protein kinase ULK1

D: Serine/threonine-protein kinase ULK1

hetero molecules

131 kDa, 4 polymers
Search similar-shape structures of this assembly by Omokage search (details)

1

A: Serine/threonine-protein kinase ULK1

hetero molecules

defined by author
Evidence: gel filtration
32.8 kDa, 1 polymers
Search similar-shape structures of this assembly by Omokage search (details)

2

B: Serine/threonine-protein kinase ULK1

hetero molecules

defined by author
32.7 kDa, 1 polymers
Search similar-shape structures of this assembly by Omokage search (details)

3

C: Serine/threonine-protein kinase ULK1

hetero molecules

defined by author
32.8 kDa, 1 polymers
Search similar-shape structures of this assembly by Omokage search (details)

4

D: Serine/threonine-protein kinase ULK1

hetero molecules

defined by author
32.6 kDa, 1 polymers
Search similar-shape structures of this assembly by Omokage search (details)

Unit cell

Length a, b, c (Å)	85.260, 109.940, 96.220
Angle α, β, γ (deg.)	90.000, 93.775, 90.000
Int Tables number	4
Space group name H-M	P12₁1

Noncrystallographic symmetry (NCS)

NCS domain:

ID	Ens-ID	Details
1	1	A
2	1	A
3	2	A
4	2	A
5	3	A
6	3	A
7	4	A
8	4	A
9	5	A
10	5	A
11	6	A
12	6	A

NCS domain segments:

Beg auth comp-ID: THR / Beg label comp-ID: THR / Auth asym-ID: A / Label asym-ID: A

Dom-ID	Component-ID	Ens-ID	End auth comp-ID	End label comp-ID	Auth seq-ID	Label seq-ID
1	1	1	ALA	ALA	8 - 280	9 - 281
2	1	1	ALA	ALA	8 - 280	9 - 281
3	2	2	LEU	LEU	8 - 278	9 - 279
4	2	2	LEU	LEU	8 - 278	9 - 279
5	3	3	ALA	ALA	8 - 280	9 - 281
6	3	3	ALA	ALA	8 - 280	9 - 281
7	4	4	ASP	ASP	8 - 279	9 - 280
8	4	4	ASP	ASP	8 - 279	9 - 280
9	5	5	ALA	ALA	8 - 280	9 - 281
10	5	5	ALA	ALA	8 - 280	9 - 281
11	6	6	ASP	ASP	8 - 279	9 - 280
12	6	6	ASP	ASP	8 - 279	9 - 280

NCS ensembles :

ID	Details
1	Local NCS retraints between domains: 1 2
2	Local NCS retraints between domains: 3 4
3	Local NCS retraints between domains: 5 6
4	Local NCS retraints between domains: 7 8
5	Local NCS retraints between domains: 9 10
6	Local NCS retraints between domains: 11 12

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Protein , 1 types, 4 molecules ABCD

#1: Protein	Serine/threonine-protein kinase ULK1 / Autophagy-related protein 1 homolog / ATG1 / hATG1 / Unc-51-like kinase 1 Mass: 32121.098 Da / Num. of mol.: 4 / Mutation: R245A, E246A 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

#1: Protein

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

Mass: 32121.098 Da / Num. of mol.: 4 / Mutation: R245A, E246A
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

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Non-polymers , 5 types, 634 molecules

#2: Chemical	ChemComp-HVH / ~{N}-[3-[[5-cyclopropyl-2-[(2-methyl-3,4-dihydro-1~{H}-isoquinolin-6-yl)amino]pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide Mass: 434.577 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C₂₅H₃₄N₆O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical	ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C₃H₈O₃
#4: Chemical	ChemComp-MG / MAGNESIUM ION Mass: 24.305 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Mg
#5: Chemical	ChemComp-PO4 / PHOSPHATE ION Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO₄
#6: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 617 / Source method: isolated from a natural source / Formula: H₂O

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Details

Has ligand of interest	Y
Has protein modification	Y

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Experiment

Experiment	Method: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

Crystal	Density Matthews: 3.5 Å³/Da / Density % sol: 64.88 %
Crystal grow	Temperature: 277.15 K / Method: vapor diffusion, hanging drop / pH: 6 / Details: 0.3-0.8 M NaAcetate pH 6, 20-26% w/v PEG3350

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Data collection

Diffraction	Mean temperature: 100 K / Serial crystal experiment: N
Diffraction source	Source: SYNCHROTRON / Site: ELETTRA / Beamline: 11.2C / Wavelength: 1 Å
Detector	Type: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 5, 2023
Radiation	Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 1 Å / Relative weight: 1
Reflection	Resolution: 2.209→85.075 Å / Num. obs: 88463 / % possible obs: 99.7 % / Redundancy: 6.6 % / CC_1/2: 0.999 / Net I/σ(I): 16.6
Reflection shell	Resolution: 2.209→2.247 Å / Mean I/σ(I) obs: 2.1 / Num. unique obs: 4401 / CC_1/2: 0.714 / % possible all: 99.2

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Processing

Software

Name	Version	Classification
REFMAC	5.8.0405	refinement
XDS		data reduction
pointless		data scaling
MOLREP		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT / Resolution: 2.209→85.075 Å / Cor.coef. F_o:F_c: 0.961 / Cor.coef. F_o:F_c free: 0.95 / SU B: 4.874 / SU ML: 0.117 / Cross valid method: FREE R-VALUE / ESU R: 0.182 / ESU R Free: 0.155
Details: Hydrogens have been added in their riding positions

	R_factor	Num. reflection	% reflection
R_free	0.2043	4466	5.049 %
R_work	0.177	83995	-
all	0.178	-	-
obs	-	88461	99.649 %

Solvent computation

Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT

Displacement parameters

B_iso mean: 40.344 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	0.246 Å²	0 Å²	-1.165 Å²
2-	-	-1.31 Å²	0 Å²
3-	-	-	1.208 Å²

Refinement step

Cycle: LAST / Resolution: 2.209→85.075 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	8649	0	164	617	9430

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.008	0.012	9164
X-RAY DIFFRACTION	r_bond_other_d	0.001	0.016	8921
X-RAY DIFFRACTION	r_angle_refined_deg	1.427	1.653	12403
X-RAY DIFFRACTION	r_angle_other_deg	0.478	1.577	20573
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	6.167	5	1129
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	10.849	5	62
X-RAY DIFFRACTION	r_dihedral_angle_other_2_deg	10.202	5	12
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	16.703	10	1663
X-RAY DIFFRACTION	r_dihedral_angle_6_deg	16.695	10	410
X-RAY DIFFRACTION	r_chiral_restr	0.071	0.2	1373
X-RAY DIFFRACTION	r_gen_planes_refined	0.008	0.02	10571
X-RAY DIFFRACTION	r_gen_planes_other	0.001	0.02	2113
X-RAY DIFFRACTION	r_nbd_refined	0.221	0.2	1792
X-RAY DIFFRACTION	r_symmetry_nbd_other	0.2	0.2	7999
X-RAY DIFFRACTION	r_nbtor_refined	0.182	0.2	4433
X-RAY DIFFRACTION	r_symmetry_nbtor_other	0.082	0.2	4900
X-RAY DIFFRACTION	r_xyhbond_nbd_refined	0.208	0.2	492
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_other	0.027	0.2	1
X-RAY DIFFRACTION	r_symmetry_nbd_refined	0.185	0.2	18
X-RAY DIFFRACTION	r_nbd_other	0.18	0.2	68
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_refined	0.123	0.2	10
X-RAY DIFFRACTION	r_mcbond_it	3.605	3.917	4390
X-RAY DIFFRACTION	r_mcbond_other	3.604	3.917	4388
X-RAY DIFFRACTION	r_mcangle_it	5.104	7.02	5485
X-RAY DIFFRACTION	r_mcangle_other	5.103	7.021	5485
X-RAY DIFFRACTION	r_scbond_it	4.977	4.498	4774
X-RAY DIFFRACTION	r_scbond_other	4.957	4.491	4767
X-RAY DIFFRACTION	r_scangle_it	7.675	7.99	6870
X-RAY DIFFRACTION	r_scangle_other	7.671	7.976	6859
X-RAY DIFFRACTION	r_lrange_it	9.143	37.897	10216
X-RAY DIFFRACTION	r_lrange_other	9.136	37.76	10072
X-RAY DIFFRACTION	r_ncsr_local_group_1	0.093	0.05	8661
X-RAY DIFFRACTION	r_ncsr_local_group_2	0.08	0.05	8785
X-RAY DIFFRACTION	r_ncsr_local_group_3	0.098	0.05	8659
X-RAY DIFFRACTION	r_ncsr_local_group_4	0.096	0.05	8607
X-RAY DIFFRACTION	r_ncsr_local_group_5	0.075	0.05	8885
X-RAY DIFFRACTION	r_ncsr_local_group_6	0.1	0.05	8617

Refine LS restraints NCS

Ens-ID	Dom-ID	Auth asym-ID	Refine-ID	Type	Rms dev position (Å)	Weight position
1	1	A	X-RAY DIFFRACTION	Local ncs	0.09334	0.05009
1	2	A	X-RAY DIFFRACTION	Local ncs	0.09334	0.05009
2	3	A	X-RAY DIFFRACTION	Local ncs	0.07977	0.05009
2	4	A	X-RAY DIFFRACTION	Local ncs	0.07977	0.05009
3	5	A	X-RAY DIFFRACTION	Local ncs	0.09812	0.05009
3	6	A	X-RAY DIFFRACTION	Local ncs	0.09812	0.05009
4	7	A	X-RAY DIFFRACTION	Local ncs	0.09611	0.05009
4	8	A	X-RAY DIFFRACTION	Local ncs	0.09611	0.05009
5	9	A	X-RAY DIFFRACTION	Local ncs	0.0755	0.05009
5	10	A	X-RAY DIFFRACTION	Local ncs	0.0755	0.05009
6	11	A	X-RAY DIFFRACTION	Local ncs	0.09981	0.05009
6	12	A	X-RAY DIFFRACTION	Local ncs	0.09981	0.05009

LS refinement shell

Resolution (Å)	R_factor R_free	Num. reflection R_free	R_factor R_work	Num. reflection R_work	Refine-ID	% reflection obs (%)
2.209-2.266	0.277	313	0.267	6128	X-RAY DIFFRACTION	99.3062
2.266-2.328	0.281	308	0.246	6047	X-RAY DIFFRACTION	99.4367
2.328-2.395	0.25	269	0.225	5915	X-RAY DIFFRACTION	99.5012
2.395-2.469	0.252	286	0.213	5727	X-RAY DIFFRACTION	99.5695
2.469-2.55	0.25	286	0.206	5495	X-RAY DIFFRACTION	99.6209
2.55-2.639	0.235	303	0.19	5338	X-RAY DIFFRACTION	99.6995
2.639-2.739	0.24	291	0.189	5160	X-RAY DIFFRACTION	99.7621
2.739-2.851	0.237	286	0.186	4926	X-RAY DIFFRACTION	99.7512
2.851-2.977	0.231	236	0.176	4806	X-RAY DIFFRACTION	99.7034
2.977-3.122	0.217	246	0.168	4573	X-RAY DIFFRACTION	99.8343
3.122-3.291	0.202	239	0.169	4321	X-RAY DIFFRACTION	99.9781
3.291-3.49	0.211	239	0.187	4101	X-RAY DIFFRACTION	99.8849
3.49-3.731	0.222	194	0.182	3898	X-RAY DIFFRACTION	99.7805
3.731-4.029	0.179	206	0.161	3580	X-RAY DIFFRACTION	99.7891
4.029-4.413	0.134	175	0.131	3333	X-RAY DIFFRACTION	99.9146
4.413-4.932	0.155	134	0.132	3018	X-RAY DIFFRACTION	99.4949
4.932-5.692	0.197	160	0.164	2660	X-RAY DIFFRACTION	99.7877
5.692-6.963	0.193	126	0.179	2256	X-RAY DIFFRACTION	99.7487
6.963-9.815	0.172	110	0.152	1732	X-RAY DIFFRACTION	99.6753
9.815-85.075	0.185	59	0.228	981	X-RAY DIFFRACTION	97.6526

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