PDB-8uoh: Crystal structure of human NUAK1-MARK3 kinase domain chimera boun...

ID or keywords:

Entry

Database: PDB / ID: 8uoh

Title

Crystal structure of human NUAK1-MARK3 kinase domain chimera bound with small molecule inhibitor #10

Components

MAP/microtubule affinity-regulating kinase 3

Keywords

TRANSFERASE/TRANSFERASE INHIBITOR / Kinase / Serine/threonine-protein kinase / NUAK1 / MARK3 / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex

Function / homology

Function and homology information

peptidyl-serine autophosphorylation / negative regulation of protein localization to nucleus / tau-protein kinase activity / negative regulation of hippo signaling / Transcriptional and post-translational regulation of MITF-M expression and activity / RAF activation / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / tau protein binding / microtubule cytoskeleton organization ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 2.15 Å

Authors

Delker, S.L. / Abendroth, J.

Funding support

1items

Citation

Journal: J.Med.Chem. / Year: 2024
Title: Discovery of UCB9386: A Potent, Selective, and Brain-Penetrant Nuak1 Inhibitor Suitable for In Vivo Pharmacological Studies.
Authors: Poullennec, K.G. / Jnoff, E. / Abendroth, J. / Bhuma, N. / Calmiano, M. / Calmus, L. / Cardenas, A. / Courade, J.P. / Delatour, C. / Hall, A. / de Haro, T. / Delker, S.L. / Demaude, T. / ...

History

Deposition	Oct 19, 2023	Deposition site: RCSB / Processing site: RCSB
Revision 1.0	Oct 23, 2024	Provider: repository / Type: Initial release
Revision 1.1	Jun 4, 2025	Group: 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

Structure viewer	Molecule: MolmilJmol/JSmol

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PDBx/mmCIF format	8uoh.cif.gz	291.3 KB	Display	PDBx/mmCIF format
PDB format	pdb8uoh.ent.gz	234.4 KB	Display	PDB format
PDBx/mmJSON format	8uoh.json.gz		Tree view	PDBx/mmJSON format
Others	Other downloads

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Validation report

Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/uo/8uoh ftp://data.pdbj.org/pub/pdb/validation_reports/uo/8uoh	HTTPS FTP

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Related structure data

Related structure data	8uoiC 8uojC 8uokC 8uolC 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

Deposited unit

A: MAP/microtubule affinity-regulating kinase 3

B: MAP/microtubule affinity-regulating kinase 3

hetero molecules

76.7 kDa, 2 polymers
Search similar-shape structures of this assembly by Omokage search (details)

1

Idetical with deposited unit
defined by author

Unit cell

Length a, b, c (Å)	61.880, 113.410, 116.640
Angle α, β, γ (deg.)	90.00, 90.00, 90.00
Int Tables number	19
Space group name H-M	P2₁2₁2₁

#1: Protein	MAP/microtubule affinity-regulating kinase 3 / C-TAK1 / cTAK1 / Cdc25C-associated protein kinase 1 / ELKL motif kinase 2 / EMK-2 / Protein kinase ...C-TAK1 / cTAK1 / Cdc25C-associated protein kinase 1 / ELKL motif kinase 2 / EMK-2 / Protein kinase STK10 / Ser/Thr protein kinase PAR-1 / Par-1a / Serine/threonine-protein kinase p78 Mass: 37872.793 Da / Num. of mol.: 2 / Mutation: I61L, V116I, G137K, F141Y, A146E, L72R Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: MARK3, CTAK1, EMK2 / Production host: Escherichia coli B (bacteria) References: UniProt: P27448, non-specific serine/threonine protein kinase
#2: Chemical	ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL Mass: 62.068 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C₂H₆O₂
#3: Chemical	ChemComp-NI / NICKEL (II) ION Mass: 58.693 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: Ni
#4: Chemical	ChemComp-X4W / (6P)-6-[(4S)-imidazo[1,2-a]pyridin-3-yl]-4-[(1R)-1-phenylethyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one Mass: 370.404 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₂₂H₁₈N₄O₂ / Feature type: SUBJECT OF INVESTIGATION
#5: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 332 / Source method: isolated from a natural source / Formula: H₂O
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: 2.68 Å³/Da / Density % sol: 54.06 %
Crystal grow	Temperature: 287 K / Method: vapor diffusion, sitting drop / pH: 7.1 Details: 8.09 mg/mL Tray302895 fine screen F2: 0.1M HEPES pH 7.1, 0.2M MgCl, 8 (%v/v) PEG 8000; protein buffer contains: 20 mM HEPES pH 7.5, 100 mM NaCl, 5 mM BME

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Data collection

Diffraction

Mean temperature: 100 K / Serial crystal experiment: N

Diffraction source

Source:

SYNCHROTRON / Site:

APS

/ Beamline: 21-ID-F / Wavelength: 0.9787 Å

Detector

Type: RAYONIX MX-225 / Detector: CCD / Date: Aug 9, 2018

Radiation

Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray

Radiation wavelength

Wavelength: 0.9787 Å / Relative weight: 1

Reflection

Resolution: 2.15→50 Å / Num. obs: 45381 / % possible obs: 99.9 % / Redundancy: 6.148 % / CC_1/2: 0.999 / R_merge(I) obs: 0.052 / R_rim(I) all: 0.057 / Net I/σ(I): 21.01

Reflection shell

Resolution (Å)	R_merge(I) obs	Num. unique obs	CC_1/2	R_rim(I) all	Diffraction-ID
2.15-2.21	0.596	3326	0.885	0.651	1
2.21-2.27	0.453	3219	0.938	0.495	1
2.27-2.33	0.366	3113	0.954	0.4	1
2.33-2.4	0.303	3054	0.966	0.331	1
2.4-2.48	0.253	2982	0.976	0.276	1
2.48-2.57	0.204	2868	0.984	0.223	1
2.57-2.67	0.157	2760	0.989	0.171	1
2.67-2.78	0.121	2665	0.993	0.132	1
2.78-2.9	0.097	2580	0.995	0.106	1
2.9-3.04	0.079	2442	0.997	0.087	1
3.04-3.21	0.061	2352	0.997	0.067	1
3.21-3.4	0.049	2234	0.998	0.053	1
3.4-3.63	0.04	2096	0.999	0.044	1
3.63-3.93	0.034	1953	0.999	0.038	1
3.93-4.3	0.029	1807	0.999	0.032	1
4.3-4.81	0.027	1649	0.999	0.03	1
4.81-5.55	0.028	1457	0.999	0.031	1
5.55-6.8	0.027	1264	0.999	0.03	1
6.8-9.62	0.024	987	0.999	0.026	1
2.15-2.21	0.022	573	0.999	0.025	1

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Processing

Software

Name	Version	Classification
PHENIX	1.14RC2_3191	refinement
XSCALE		data scaling
XDS		data reduction
PHASER		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT / Resolution: 2.15→42.44 Å / SU ML: 0.25 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 24.13 / Stereochemistry target values: ML

	R_factor	Num. reflection	% reflection
R_free	0.22	1981	4.37 %
R_work	0.175	-	-
obs	0.177	45366	99.9 %

Solvent computation

Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL

Displacement parameters

B_iso mean: 48.48 Å²

Refinement step

Cycle: LAST / Resolution: 2.15→42.44 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	2659	2650	65	332	5706

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 (%)
2.15-2.2038	0.294	121	0.2289	3076	X-RAY DIFFRACTION	100
2.2038-2.2634	0.268	136	0.215	3053	X-RAY DIFFRACTION	100
2.2634-2.33	0.3095	141	0.2087	3040	X-RAY DIFFRACTION	100
2.33-2.4052	0.2456	154	0.2077	3043	X-RAY DIFFRACTION	100
2.4052-2.4911	0.2791	124	0.2039	3100	X-RAY DIFFRACTION	100
2.4911-2.5908	0.268	146	0.2011	3071	X-RAY DIFFRACTION	100
2.5908-2.7087	0.2637	129	0.2016	3077	X-RAY DIFFRACTION	100
2.7087-2.8515	0.2567	149	0.2007	3064	X-RAY DIFFRACTION	100
2.8515-3.0301	0.261	157	0.2105	3046	X-RAY DIFFRACTION	100
3.0301-3.264	0.2571	157	0.1931	3107	X-RAY DIFFRACTION	100
3.264-3.5923	0.2426	136	0.1795	3120	X-RAY DIFFRACTION	100
3.5923-4.1118	0.1946	143	0.1509	3126	X-RAY DIFFRACTION	100
4.1118-5.1789	0.1623	148	0.1344	3159	X-RAY DIFFRACTION	100
5.1789-42.44	0.1732	140	0.1637	3303	X-RAY DIFFRACTION	99

Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

ID	L11 (°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)
1	6.1639	0.6181	1.0995	5.8819	3.566	6.3116	0.1894	-0.6095	0.1856	0.5648	-0.2741	0.4531	-0.1025	-0.5145	0.1194	0.3776	-0.0462	0.0892	0.3926	-0.0286	0.3265	-9.052	53.8692	6.4237
2	4.5277	0.3723	1.3072	4.4085	0.4521	2.8773	-0.2453	0.1539	0.7681	-0.1367	0.1207	0.0791	-0.4516	0.0115	0.1505	0.2915	-0.0009	-0.0014	0.2981	-0.0035	0.3237	-0.6713	65.1327	-0.1116
3	5.0906	0.8009	2.3757	2.8153	0.9264	3.3259	0.1393	-0.2042	-0.3712	0.39	0.0182	-0.1651	-0.0041	-0.043	-0.1663	0.2398	0.0182	0.0014	0.2721	0.0118	0.2963	10.1127	65.1919	12.4735
4	1.9338	3.5584	3.7793	7.4098	6.7592	8.7962	0.0846	-0.2098	0.6319	-0.1262	-0.855	1.2839	-0.3283	-0.8908	0.6773	0.4515	0.0408	-0.0168	0.4712	-0.0056	0.5381	-1.2666	74.6112	11.2989
5	4.8909	-1.9957	0.4088	5.0313	-0.5074	2.9049	0.0479	-0.1006	0.2812	0.6988	0.0178	-0.4843	-0.2437	0.3808	-0.0567	0.3501	-0.1205	-0.085	0.3696	0.015	0.3322	16.1292	79.7327	22.3962
6	1.6679	2.2042	1.6617	4.5297	3.542	3.1265	-0.1215	0.273	-0.2472	-0.2361	0.3925	-0.6312	-0.0861	0.5946	-0.2765	0.3309	-0.0014	0.0685	0.4894	0.0377	0.4045	17.8203	61.3152	0.2165
7	4.3539	-1.095	5.2524	2.7881	0.3798	7.4983	-0.2134	-0.142	0.1603	0.3693	-0.1515	-0.4066	-0.2774	0.0089	0.3349	0.4018	-0.0031	-0.0008	0.3261	-0.0065	0.2978	4.9958	52.4205	-3.8943
8	1.7573	0.0855	-0.5979	3.1439	1.7358	3.5465	-0.1438	-0.0769	-0.3222	0.1989	0.008	0.246	0.2695	-0.1575	0.1015	0.2975	-0.0218	0.0124	0.2325	0.0367	0.2596	10.2242	15.8413	13.2288
9	1.3431	0.9458	0.4028	2.8732	2.6372	3.3276	0.0176	-0.0825	-0.0964	0.0921	0.0542	0.0136	0.0228	-0.0042	-0.0848	0.3031	0.03	0.0166	0.256	0.0405	0.2518	13.5397	29.0945	23.1276
10	6.9655	2.0884	-0.5739	3.2635	0.0379	2.0494	0.0133	-0.6002	0.1573	0.0217	-0.0347	0.2514	-0.0981	-0.047	0.0097	0.3324	0.1103	-0.0123	0.328	-0.0382	0.2468	6.4092	36.4691	39.6822
11	0.8855	-1.1809	-2.4354	3.2456	4.6618	8.0102	0.0694	0.0827	0.1318	-0.4139	0.0341	-0.0499	-0.7352	0.0383	-0.1061	0.3769	0.0322	-0.0332	0.2703	0.0579	0.3142	19.0201	35.88	11.9342

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection details
1	X-RAY DIFFRACTION	1	CHAIN 'A' AND (RESID 43 THROUGH 75 )
2	X-RAY DIFFRACTION	2	CHAIN 'A' AND (RESID 76 THROUGH 123 )
3	X-RAY DIFFRACTION	3	CHAIN 'A' AND (RESID 124 THROUGH 194 )
4	X-RAY DIFFRACTION	4	CHAIN 'A' AND (RESID 195 THROUGH 215 )
5	X-RAY DIFFRACTION	5	CHAIN 'A' AND (RESID 216 THROUGH 287 )
6	X-RAY DIFFRACTION	6	CHAIN 'A' AND (RESID 288 THROUGH 351 )
7	X-RAY DIFFRACTION	7	CHAIN 'A' AND (RESID 352 THROUGH 369 )
8	X-RAY DIFFRACTION	8	CHAIN 'B' AND (RESID 43 THROUGH 109 )
9	X-RAY DIFFRACTION	9	CHAIN 'B' AND (RESID 110 THROUGH 207 )
10	X-RAY DIFFRACTION	10	CHAIN 'B' AND (RESID 208 THROUGH 287 )
11	X-RAY DIFFRACTION	11	CHAIN 'B' AND (RESID 288 THROUGH 370 )

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