PDB-8c3g: Crystal structure of DYRK1A in complex with AZ191

ID or keywords:

Entry

Database: PDB / ID: 8c3g

Title

Crystal structure of DYRK1A in complex with AZ191

Components

Dual specificity tyrosine-phosphorylation-regulated kinase 1A

DYRK1A

Keywords

TRANSFERASE /

Kinase /

diabetes /

kinase inhibitor

Function / homology

Function and homology information

histone H3T45 kinase activity / positive regulation of protein deacetylation / peptidyl-serine autophosphorylation / negative regulation of DNA methylation-dependent heterochromatin formation /

dual-specificity kinase / [RNA-polymerase]-subunit kinase / negative regulation of microtubule polymerization /

tau-protein kinase activity / negative regulation of DNA damage response, signal transduction by p53 class mediator / negative regulation of mRNA splicing, via spliceosome ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 2.08 Å

Authors

Grygier, P. / Pustelny, K. / Dubin, G. / Czarna, A.

Funding support

Poland, 2items

Citation

Journal: To Be Published
Title: Structural perspective on the design of selective DYRK1B inhibitors
Authors: Grygier, P. / Pustelny, K. / Dubin, G. / Czarna, A.

History

Deposition	Dec 23, 2022	Deposition site: PDBE / Processing site: PDBE
Revision 1.0	Jan 10, 2024	Provider: repository / Type: Initial release

Structure viewer	Molecule: MolmilJmol/JSmol

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Download

PDBx/mmCIF format	8c3g.cif.gz	645.6 KB	Display	PDBx/mmCIF format
PDB format	pdb8c3g.ent.gz	474 KB	Display	PDB format
PDBx/mmJSON format	8c3g.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/c3/8c3g ftp://data.pdbj.org/pub/pdb/validation_reports/c3/8c3g	HTTPS FTP

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Related structure data

Related structure data	8c2zC 6eisS S: Starting model for refinement 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	#236 - Aug 2019 Cyclin and Cyclin-dependent Kinase similarity (1)

Deposited unit

A: Dual specificity tyrosine-phosphorylation-regulated kinase 1A

B: Dual specificity tyrosine-phosphorylation-regulated kinase 1A

C: Dual specificity tyrosine-phosphorylation-regulated kinase 1A

D: Dual specificity tyrosine-phosphorylation-regulated kinase 1A

hetero molecules

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

1

Idetical with deposited unit
defined by author&software
Evidence: gel filtration

Unit cell

Length a, b, c (Å)	87.064, 87.445, 228.888
Angle α, β, γ (deg.)	90.000, 90.000, 90.000
Int Tables number	19
Space group name H-M	P2₁2₁2₁
Space group name Hall	P2ac2ab

#1: Protein	Dual specificity tyrosine-phosphorylation-regulated kinase 1A / DYRK1A / Dual specificity YAK1-related kinase / HP86 / Protein kinase minibrain homolog / MNBH / hMNB Mass: 43311.770 Da / Num. of mol.: 4 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: DYRK1A, DYRK, MNB, MNBH / Production host: Escherichia coli (E. coli) References: UniProt: Q13627, [RNA-polymerase]-subunit kinase, dual-specificity kinase
#2: Chemical	ChemComp-QS0 / N-[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]-4-(1-methylpyrrolo[2,3-c]pyridin-3-yl)pyrimidin-2-amine / N-[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]-4-(1-methylpyrrolo[2,3-c]pyridin-3-yl)pyrimidin-2-amine Mass: 429.517 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C₂₄H₂₇N₇O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical	... ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol Mass: 62.068 Da / Num. of mol.: 32 / Source method: isolated from a natural source / Formula: C₂H₆O₂
#4: Chemical	ChemComp-SO4 / SULFATE ION / Sulfate Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO₄
#5: Water	ChemComp-HOH / water / Water Mass: 18.015 Da / Num. of mol.: 804 / Source method: isolated from a natural source / Formula: H₂O
Has ligand of interest	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: 2.52 Å³/Da / Density % sol: 51.2 %
Crystal grow	Temperature: 293.15 K / Method: vapor diffusion, sitting drop Details: 0.1 M HEPES pH 7.5, 10% PEG 8000, 8% ethylene glycol, 0.1 M ammonium sulfate

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Data collection

Diffraction	Mean temperature: 100 K / Serial crystal experiment: N
Diffraction source	Source: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
Detector	Type: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Oct 22, 2021
Radiation	Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 0.9184 Å / Relative weight: 1
Reflection	Resolution: 2.08→47.97 Å / Num. obs: 104770 / % possible obs: 99.3 % / Redundancy: 5.1 % / B_iso Wilson estimate: 35.43 Å² / CC_1/2: 0.998 / R_merge(I) obs: 0.114 / R_pim(I) all: 0.055 / R_rim(I) all: 0.127 / Χ²: 1.03 / Net I/σ(I): 9 / Num. measured all: 536933
Reflection shell	Resolution: 2.08→2.12 Å / % possible obs: 99.8 % / Redundancy: 5.3 % / R_merge(I) obs: 1.408 / Num. measured all: 27325 / Num. unique obs: 5138 / CC_1/2: 0.464 / R_pim(I) all: 0.672 / R_rim(I) all: 1.566 / Χ²: 1.09 / Net I/σ(I) obs: 1.3

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Processing

Software

Name	Version	Classification
PHENIX	1.20.1_4487	refinement
Aimless		data scaling
XDS		data reduction
PHASER		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT
Starting model: 6EIS

6eis

Resolution: 2.08→43.53 Å / SU ML: 0.2874 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 27.5616
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2

	R_factor	Num. reflection	% reflection
R_free	0.2373	5255	5.02 %
R_work	0.1941	99392	-
obs	0.1963	104647	99.07 %

Solvent computation

Shrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL

Displacement parameters

B_iso mean: 49.32 Å²

Refinement step

Cycle: LAST / Resolution: 2.08→43.53 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	10812	0	266	804	11882

Refine LS restraints

Refine-ID	Type	Dev ideal	Number
X-RAY DIFFRACTION	f_bond_d	0.008	11358
X-RAY DIFFRACTION	f_angle_d	0.959	15325
X-RAY DIFFRACTION	f_chiral_restr	0.0548	1629
X-RAY DIFFRACTION	f_plane_restr	0.0113	1995
X-RAY DIFFRACTION	f_dihedral_angle_d	15.7253	4255

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 (%)
2.08-2.1	0.3488	158	0.3112	3263	X-RAY DIFFRACTION	99.56
2.1-2.13	0.3107	171	0.3034	3343	X-RAY DIFFRACTION	99.57
2.13-2.15	0.3545	152	0.295	3262	X-RAY DIFFRACTION	99.65
2.15-2.18	0.3349	185	0.286	3309	X-RAY DIFFRACTION	99.71
2.18-2.21	0.3358	198	0.2813	3261	X-RAY DIFFRACTION	99.63
2.21-2.24	0.2993	156	0.2702	3337	X-RAY DIFFRACTION	99.09
2.24-2.27	0.3181	178	0.2738	3248	X-RAY DIFFRACTION	99.74
2.27-2.31	0.3432	169	0.2732	3274	X-RAY DIFFRACTION	98.97
2.31-2.34	0.3293	186	0.2631	3259	X-RAY DIFFRACTION	98.4
2.34-2.38	0.282	155	0.2544	3317	X-RAY DIFFRACTION	99.74
2.38-2.42	0.3169	159	0.2511	3362	X-RAY DIFFRACTION	99.86
2.42-2.47	0.2893	158	0.225	3302	X-RAY DIFFRACTION	100
2.47-2.51	0.335	171	0.2296	3309	X-RAY DIFFRACTION	99.89
2.51-2.56	0.273	185	0.2342	3326	X-RAY DIFFRACTION	99.91
2.56-2.62	0.2776	146	0.2276	3333	X-RAY DIFFRACTION	99.74
2.62-2.68	0.2753	166	0.2175	3319	X-RAY DIFFRACTION	99.77
2.68-2.75	0.2853	204	0.2118	3286	X-RAY DIFFRACTION	99.52
2.75-2.82	0.3048	181	0.2115	3335	X-RAY DIFFRACTION	99.52
2.82-2.91	0.2771	161	0.2018	3310	X-RAY DIFFRACTION	99.2
2.91-3	0.2513	174	0.1992	3277	X-RAY DIFFRACTION	97.82
3-3.11	0.2364	180	0.1961	3250	X-RAY DIFFRACTION	98.06
3.11-3.23	0.2492	198	0.1954	3324	X-RAY DIFFRACTION	99.66
3.23-3.38	0.2216	168	0.1848	3337	X-RAY DIFFRACTION	99.4
3.38-3.56	0.226	201	0.1696	3304	X-RAY DIFFRACTION	99.57
3.56-3.78	0.2071	160	0.1616	3378	X-RAY DIFFRACTION	99.35
3.78-4.07	0.1867	212	0.1498	3292	X-RAY DIFFRACTION	98.76
4.07-4.48	0.187	170	0.1398	3272	X-RAY DIFFRACTION	96.52
4.48-5.13	0.1906	186	0.147	3382	X-RAY DIFFRACTION	98.37
5.13-6.46	0.222	179	0.1897	3372	X-RAY DIFFRACTION	98.12
6.46-43.53	0.1841	188	0.1786	3449	X-RAY DIFFRACTION	95.53

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	3.39368138292	0.0422099770845	0.507493490086	2.76815636264	-0.182112933296	4.29485522032	0.13533528544	-0.32207592801	-0.283852397812	0.24408151838	0.00567212955794	-0.320109597291	0.342225729904	0.275918401632	-0.136799956348	0.232309618438	0.00279376605363	-0.0144422799581	0.245710585733	0.0241666438991	0.252027536952	-9.79485313723	-31.6242876196	21.7604065423
2	2.17574656883	1.10585013976	-1.52233080802	1.15746386952	-0.483055190749	2.76195198188	-0.0594337779077	0.116720019515	-0.0350471144296	-0.103011432594	0.0847947601955	0.0515948914323	0.121788129875	-0.143415751613	-0.0103068920558	0.181623815272	0.0135042621034	-0.0298938899229	0.172478800448	-0.00522373424884	0.238918459725	-7.87878113756	-22.1713691351	5.96176049868
3	2.62078906672	1.00565146147	0.283012610781	1.30470265549	0.406343311516	2.33687705372	0.103007242014	-0.216158134696	0.138868828866	0.0786403883566	-0.0684580123737	0.00476399635035	-0.257196537051	0.111971597932	-0.0393449846865	0.257242198643	-0.00689706024033	0.0217613445011	0.191821211022	-0.0012850624197	0.235177445618	7.36524519843	-6.16965717188	9.59979436398
4	3.11898649894	1.14847726865	-0.235034945955	2.65623590548	1.13268668386	3.23058032309	-0.120449323316	0.351900462812	-0.016735675802	-0.144385868342	0.166213789193	0.145290925273	-0.0973787403825	-0.0288298106375	-0.0562659131092	0.229215184661	-0.00391973672936	0.0133252879933	0.194418874768	0.0578528540986	0.205044529081	5.70653488841	-8.57397032827	-6.56859049732
5	3.28573113468	-1.19818844764	-0.97963328072	2.86402519381	1.91643508112	2.63051643815	0.143822764613	-0.188173909266	-0.0432005405153	-0.0577720835515	-0.549995516014	0.596049506632	-0.198068688772	-0.587377105841	0.360215670666	0.424870109501	-0.048265717526	-0.00908523219822	0.691757883563	-0.214576231659	0.430333669927	-22.9597306153	15.4929408734	40.0481185798
6	2.24526420404	0.0586276805744	-0.867005281192	1.40320205771	-0.647682108045	4.49948090216	0.247288511533	-0.282354172622	0.347060403517	-0.00772902615839	-0.223396156152	0.138391313967	-0.279149530294	0.454188198948	-0.0087615681017	0.408761471434	-0.0400751224259	-0.018469486559	0.400386812473	-0.155815051129	0.385493037988	-11.993636842	18.4923224723	25.99335159
7	3.85947695822	-0.447894614626	0.40684993949	1.80349848772	-1.19453534885	4.06270562289	0.29223676711	0.325983047014	0.219701584467	-0.732450238084	-0.0821878195728	0.0281292574847	-0.0142462361855	0.0332050712811	-0.177740510549	0.594972367053	0.077486411851	0.0119614927347	0.260607295564	-0.0166878923124	0.340783955941	-14.8596532601	18.3415663214	4.52535310954
8	4.05978278306	-1.125389039	-1.17808462242	2.13890922201	0.0783010139234	3.81931029433	0.036040654564	-0.690375205677	0.297229619955	-0.010292149454	0.200856725928	-0.0350465589204	-0.217622869444	0.0655504367822	-0.231303469977	0.242973122303	0.0221084228834	-0.0205638518829	0.508173532133	-0.0639581453372	0.295104689899	7.94825721602	-9.42612483396	37.0651768874
9	1.32954967815	1.36400340813	-1.20351611692	1.91276766929	0.0414143037015	2.75671694206	0.0613695248405	-0.621407650637	-0.0721214896502	0.0591452782951	-0.00601111465568	-0.010621616827	0.218045637489	-0.0441443098417	-0.0116180935148	0.329869839555	0.070605630609	-0.00896949375914	0.857721501464	0.0470257855908	0.307031907044	-1.65281426569	-18.407568834	52.1895556828
10	1.47542026365	0.468964315864	0.8154294884	0.911114274732	0.59274994259	3.95639984192	0.15103343322	-0.680035547158	-0.257372707581	0.199740362009	-0.110386120477	0.123756878625	0.614853885475	-0.510564450218	-0.038411034349	0.451657314108	-0.0788707769238	-0.0117252272088	0.990494977952	0.191975620061	0.391512504702	-12.6732122196	-31.5089440371	55.6918612125
11	3.88210415826	-0.590645244564	0.426049697481	3.50016789576	-0.317726496569	2.02355627318	-0.235403249091	-0.119587214581	0.623202905799	-0.0201660119383	-0.088665344194	-0.0870639468681	-0.368733715918	0.126532259451	0.339412461769	0.30282460804	0.0254514142165	-0.0500801368373	0.431998291057	-0.0677203541813	0.352957694748	-38.3702964861	-1.56522201871	18.1430195521
12	1.3834728995	0.0832041095484	-0.572249912652	1.75098593898	-0.488841399287	3.59108960621	-0.0244421674245	-0.186602518755	0.0175178731622	0.113438748811	-0.0666015111457	0.123826640438	0.213031515086	-0.110121180834	0.10109588946	0.208917913967	-0.0417896035515	-0.00956421565786	0.368898710849	-0.0637829390335	0.293904741337	-40.9895832295	-12.7170779895	31.7882891313
13	3.18444209336	0.13650335121	-0.581356414342	2.08210384938	0.0201537005026	2.64554339613	0.0112781326463	-1.49882678909	0.193948207237	0.661034115008	0.100130858495	-0.020382876308	0.172618236074	0.482991708524	-0.0545861234176	0.480562505974	-0.0437115794055	0.00068152660702	1.10110981234	-0.167751270492	0.390758006927	-42.3736635136	-9.82584832276	52.6546736142

Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

ID	Refine TLS-ID	Selection details	Auth asym-ID	Label asym-ID	Auth seq-ID	Label seq-ID
1	1	chain 'A' and (resid 134 through 211 )	A	A	134 - 211	1 - 78
2	2	chain 'A' and (resid 212 through 302 )	A	A	212 - 302	79 - 169
3	3	chain 'A' and (resid 303 through 405 )	A	A	303 - 405	170 - 272
4	4	chain 'A' and (resid 406 through 480 )	A	A	406 - 480	273 - 344
5	5	chain 'B' and (resid 134 through 211 )	B	B	134 - 211	1 - 78
6	6	chain 'B' and (resid 212 through 320 )	B	B	212 - 320	79 - 187
7	7	chain 'B' and (resid 322 through 480 )	B	B	322 - 480	189 - 333
8	8	chain 'C' and (resid 134 through 239 )	C	C	134 - 239	1 - 106
9	9	chain 'C' and (resid 240 through 320 )	C	C	240 - 320	107 - 187
10	10	chain 'C' and (resid 322 through 480 )	C	C	322 - 480	189 - 341
11	11	chain 'D' and (resid 134 through 212 )	D	D	134 - 212	1 - 79
12	12	chain 'D' and (resid 213 through 320 )	D	D	213 - 320	80 - 187
13	13	chain 'D' and (resid 322 through 480 )	D	D	322 - 480	189 - 337

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