PDB-8w4q: Crystal structure of PDE4D complexed with CX-4945

ID or keywords:

Entry

Database: PDB / ID: 8w4q

Title

Crystal structure of PDE4D complexed with CX-4945

Components

cAMP-specific 3',5'-cyclic phosphodiesterase 4D

Keywords

HYDROLASE / PDE4D / Complex / CX-4945 / Inhibitor

Function / homology

Function and homology information

signaling receptor regulator activity / negative regulation of heart contraction / negative regulation of relaxation of cardiac muscle / 3',5'-cyclic-AMP phosphodiesterase / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of interleukin-5 production / establishment of endothelial barrier / heterocyclic compound binding / regulation of cardiac muscle cell contraction / beta-2 adrenergic receptor binding ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 1.55 Å

Authors

Liu, J.Y. / Li, M.J. / Xu, Y.C.

Funding support

1items

Citation

Journal: Eur.J.Med.Chem. / Year: 2023
Title: Drug repurposing and structure-based discovery of new PDE4 and PDE5 inhibitors.
Authors: Liu, J. / Zhang, X. / Chen, G. / Shao, Q. / Zou, Y. / Li, Z. / Su, H. / Li, M. / Xu, Y.

History

Deposition	Aug 24, 2023	Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0	Nov 22, 2023	Provider: repository / Type: Initial release

Structure viewer	Molecule: MolmilJmol/JSmol

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Download

PDBx/mmCIF format	8w4q.cif.gz	276.5 KB	Display	PDBx/mmCIF format
PDB format	pdb8w4q.ent.gz	223.2 KB	Display	PDB format
PDBx/mmJSON format	8w4q.json.gz		Tree view	PDBx/mmJSON format
Others	Other downloads

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Validation report

Summary document	8w4q_validation.pdf.gz	992.7 KB	Display	wwPDB validaton report
Full document	8w4q_full_validation.pdf.gz	999.4 KB	Display
Data in XML	8w4q_validation.xml.gz	24.6 KB	Display
Data in CIF	8w4q_validation.cif.gz	34.5 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/w4/8w4q ftp://data.pdbj.org/pub/pdb/validation_reports/w4/8w4q	HTTPS FTP

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Related structure data

Related structure data	8k4cC 8k4hC 8w4rC 8w4sC 8w4tC 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	#152 - Aug 2012 cAMP-dependent Protein Kinase similarity (8) #44 - Aug 2003 Calmodulin similarity (1) #196 - Apr 2016 Lead Poisoning similarity (1) #28 - Apr 2002 Anthrax Toxin similarity (1)

Deposited unit

A: cAMP-specific 3',5'-cyclic phosphodiesterase 4D

B: cAMP-specific 3',5'-cyclic phosphodiesterase 4D

hetero molecules

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

1

Idetical with deposited unit
defined by author
Evidence: gel filtration

Unit cell

Length a, b, c (Å)	57.509, 79.990, 162.723
Angle α, β, γ (deg.)	90.00, 90.00, 90.00
Int Tables number	19
Space group name H-M	P2₁2₁2₁

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Protein , 1 types, 2 molecules AB

#1: Protein	cAMP-specific 3',5'-cyclic phosphodiesterase 4D / PDE4D / DPDE3 / PDE43 Mass: 40096.355 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PDE4D, DPDE3 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) References: UniProt: Q08499, 3',5'-cyclic-AMP phosphodiesterase

#1: Protein

cAMP-specific 3',5'-cyclic phosphodiesterase 4D / PDE4D / DPDE3 / PDE43

Mass: 40096.355 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.)

Homo sapiens (human) / Gene: PDE4D, DPDE3 / Production host:

Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: Q08499, 3',5'-cyclic-AMP phosphodiesterase

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Non-polymers , 5 types, 121 molecules

#2: Chemical	ChemComp-MG / MAGNESIUM ION Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#3: Chemical	ChemComp-ZN / ZINC ION Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical	ChemComp-3NG / 5-[(3-chlorophenyl)amino]benzo[c][2,6]naphthyridine-8-carboxylic acid Mass: 349.770 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₁₉H₁₂ClN₃O₂ / Feature type: SUBJECT OF INVESTIGATION / Comment: chemotherapy, inhibitor*YM
#5: Chemical	ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL Mass: 62.068 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C₂H₆O₂
#6: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 109 / Source method: isolated from a natural source / Formula: H₂O

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Details

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: 2.33 Å³/Da / Density % sol: 47.29 %
Crystal grow	Temperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7 Details: 0.1 M HEPES, 0.2 M MgCl2, 10 % (v/v) Isopropanol, 30 % (v/v) Ethylene glycol, 18 % (w/v) PEG3350

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Data collection

Diffraction	Mean temperature: 100 K / Serial crystal experiment: N
Diffraction source	Source: SYNCHROTRON / Site: SSRF / Beamline: BL10U2 / Wavelength: 0.979 Å
Detector	Type: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Mar 28, 2023
Radiation	Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 0.979 Å / Relative weight: 1
Reflection	Resolution: 1.55→28.32 Å / Num. obs: 202163 / % possible obs: 95.71 % / Redundancy: 2 % / CC_1/2: 0.997 / Net I/σ(I): 11.68
Reflection shell	Resolution: 1.55→1.603 Å / Num. unique obs: 10838 / CC_1/2: 0.869

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Processing

Software

Name	Version	Classification
PHENIX	1.17.1_3660	refinement
XDS		data reduction
PHASER		phasing
SCALA		data scaling

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT / Resolution: 1.55→28.32 Å / SU ML: 0.2 / Cross valid method: THROUGHOUT / σ(F): 1.91 / Phase error: 25.55 / Stereochemistry target values: ML

	R_factor	Num. reflection	% reflection
R_free	0.2397	10036	4.96 %
R_work	0.2256	-	-
obs	0.2263	202163	95.69 %

Solvent computation

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

Refinement step

Cycle: LAST / Resolution: 1.55→28.32 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	5112	0	78	109	5299

Refine LS restraints

Refine-ID	Type	Dev ideal	Number
X-RAY DIFFRACTION	f_bond_d	0.005	5294
X-RAY DIFFRACTION	f_angle_d	0.707	7210
X-RAY DIFFRACTION	f_dihedral_angle_d	5.258	740
X-RAY DIFFRACTION	f_chiral_restr	0.042	839
X-RAY DIFFRACTION	f_plane_restr	0.005	925

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 (%)
1.55-1.57	0.3336	321	0.3247	6672	X-RAY DIFFRACTION	100
1.57-1.58	0.335	339	0.3141	6633	X-RAY DIFFRACTION	100
1.58-1.6	0.2879	368	0.298	6752	X-RAY DIFFRACTION	100
1.6-1.62	0.3468	346	0.2922	6641	X-RAY DIFFRACTION	100
1.62-1.64	0.3152	371	0.2989	6732	X-RAY DIFFRACTION	100
1.64-1.67	0.2841	326	0.2964	6709	X-RAY DIFFRACTION	100
1.67-1.69	0.3111	320	0.2803	6693	X-RAY DIFFRACTION	100
1.69-1.72	0.2948	385	0.277	6616	X-RAY DIFFRACTION	100
1.72-1.74	0.3367	358	0.282	6725	X-RAY DIFFRACTION	100
1.74-1.77	0.2764	371	0.2654	6602	X-RAY DIFFRACTION	100
1.77-1.8	0.2614	345	0.2556	6688	X-RAY DIFFRACTION	100
1.8-1.84	0.25	331	0.25	6696	X-RAY DIFFRACTION	100
1.84-1.87	0.2962	352	0.2528	6742	X-RAY DIFFRACTION	100
1.87-1.91	0.25	290	0.25	6739	X-RAY DIFFRACTION	100
1.91-1.95	0.2649	277	0.255	4448	X-RAY DIFFRACTION	67
1.95-2	0.2864	420	0.2532	6644	X-RAY DIFFRACTION	100
2-2.05	0.2371	336	0.2452	6738	X-RAY DIFFRACTION	100
2.05-2.1	0.2642	145	0.2356	3590	X-RAY DIFFRACTION	53
2.1-2.16	0.2727	336	0.2312	6690	X-RAY DIFFRACTION	100
2.16-2.23	0.2476	397	0.2321	6658	X-RAY DIFFRACTION	100
2.23-2.31	0.277	187	0.2345	4436	X-RAY DIFFRACTION	66
2.31-2.4	0.2501	395	0.2282	6700	X-RAY DIFFRACTION	100
2.4-2.51	0.2401	383	0.2279	6615	X-RAY DIFFRACTION	100
2.51-2.65	0.219	344	0.2249	6717	X-RAY DIFFRACTION	100
2.65-2.81	0.2753	357	0.2226	6692	X-RAY DIFFRACTION	100
2.81-3.03	0.2236	327	0.2304	6705	X-RAY DIFFRACTION	100
3.03-3.33	0.2429	361	0.2188	6699	X-RAY DIFFRACTION	100
3.33-3.81	0.2125	304	0.2109	6200	X-RAY DIFFRACTION	92
3.81-4.8	0.1931	326	0.189	6368	X-RAY DIFFRACTION	95
4.8-28.32	0.2162	318	0.2064	6587	X-RAY DIFFRACTION	98

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	5.416	0.2323	1.0067	5.1155	-1.4716	4.062	0.4433	0.6308	0.4217	-1.0953	-0.2434	0.2194	-1.0411	-0.5765	-0.1996	0.7171	0.2182	0.0457	0.4255	0.0268	0.2694	11.1042	91.8863	13.2767
2	1.2965	-0.7996	-0.7218	2.9728	1.3578	3.3994	0.2231	0.1915	0.2493	-0.4401	-0.2062	0.3145	-0.6437	-0.6006	-0.0232	0.2781	0.1206	0.005	0.2661	0.0213	0.2422	8.0217	91.3637	27.2267
3	2.5736	0.11	0.8205	1.4178	-0.0648	5.8796	-0.0522	0.1096	0.024	-0.0084	0.1274	-0.4114	-0.1351	0.8129	-0.0672	0.1762	-0.0214	0.0374	0.2547	-0.0333	0.3063	28.8379	85.774	38.6751
4	5.0569	-1.9241	0.0703	4.466	-0.1348	2.7413	0.2064	-0.0971	0.3882	-0.0953	-0.0844	0.0197	-0.673	-0.1897	-0.1053	0.2853	0.0236	0.07	0.1767	-0.0106	0.1926	12.819	96.7484	38.0186
5	5.5279	-5.5067	-2.2299	9.9037	2.101	5.9789	-0.168	-0.1427	-0.2999	0.341	-0.0043	0.4781	-0.0461	-0.6001	0.1937	0.1764	-0.0136	0.026	0.2594	0.0141	0.2324	7.561	87.4255	41.7174
6	0.8873	0.0472	-0.5731	2.3775	0.0673	2.6301	-0.017	-0.0528	-0.2676	0.2547	-0.1154	0.4762	0.505	-0.6042	0.1147	0.2389	-0.107	0.0431	0.3015	-0.0059	0.3333	7.2912	72.9853	33.1556
7	5.4985	0.132	2.6742	3.3327	0.3986	4.9325	0.0366	0.1211	0.1993	-0.3892	-0.0025	-0.425	-0.0905	0.9033	-0.0304	0.2649	0.0123	0.1427	0.3172	0.0095	0.2802	30.111	81.7188	20.7106
8	3.211	0.8608	2.1918	3.6627	2.6348	5.5996	-0.0575	0.078	-0.1638	0.1283	0.392	-0.6144	0.4776	1.1393	-0.3163	0.3218	0.1192	0.0486	0.4198	-0.0136	0.3755	33.0047	73.1346	23.8012
9	3.7288	-1.1002	-1.452	3.6055	0.6057	6.1843	-0.1008	0.3754	-0.5892	-0.2035	-0.2916	0.1609	0.9173	-0.5331	0.3455	0.3435	-0.0557	0.0162	0.2124	-0.04	0.2857	13.4174	68.5482	18.7118
10	0.6422	-0.2858	0.3688	2.4315	-1.205	0.9969	-0.257	-0.7233	0.2296	0.0216	0.0185	-0.5927	0.2995	1.6175	0.1964	0.5513	0.5378	-0.1362	1.5215	-0.2977	0.558	35.13	87.1606	79.3994
11	2.3076	0.4853	-0.8343	0.8982	0.5486	1.8155	-0.8157	-0.6285	0.2448	0.394	0.7308	-0.5192	0.6619	2.1518	-0.1016	0.424	0.7409	0.0567	1.1492	-0.2938	0.3603	35.4502	82.6283	66.2787
12	2.7116	-0.1271	0.5451	3.0202	0.8345	7.7546	-0.0804	-0.0441	0.3978	0.0076	0.186	0.0117	-0.5275	-0.4553	-0.1035	0.1957	0.0424	0.0159	0.2274	-0.0065	0.2436	17.2132	92.7895	54.1683
13	3.4783	-1.8258	-0.2685	2.6852	-0.4124	1.6712	-0.1379	-0.249	0.3957	-0.2273	0.2945	-0.7461	0.0586	1.1465	-0.1656	0.2706	0.0838	0.0154	0.6608	-0.1947	0.408	35.9905	87.977	54.336
14	5.7944	-2.335	-1.6264	5.0611	1.7921	2.6426	-0.4696	-0.0632	-0.7038	0.1618	0.0707	-0.0759	1.0946	0.9694	0.4342	0.511	0.2527	0.038	0.456	-0.0334	0.2822	32.0453	77.8853	53.2183
15	0.9257	0.072	-0.6171	2.7386	1.4967	1.4381	-1.2637	0.051	-0.4733	0.0096	0.8615	0.2346	1.9589	-0.086	0.3993	1.4089	0.4243	0.3685	0.2181	-0.065	0.4284	21.9795	69.4687	63.5677
16	1.36	0.27	0.266	1.9084	-1.6371	5.6579	-0.3377	-0.3894	0.1396	0.6647	0.6111	0.0308	-0.7654	-0.2187	-0.257	0.5188	0.267	0.0096	0.4292	-0.0875	0.3023	14.7973	93.6726	72.9062
17	2.4562	-0.3877	0.4315	5.245	-2.8209	5.7839	-0.0044	0.4442	0.3586	0.0604	-0.0359	0.1954	0.0783	-1.0848	0.0603	0.4969	0.173	0.0743	0.5325	0.0076	0.3344	6.2042	90.0373	70.7833
18	1.3689	-0.6162	-0.1608	1.2304	0.9087	0.7063	-0.6298	-0.6669	-0.3594	-0.2623	0.3087	-0.0303	1.9199	0.4046	0.349	1.4571	0.424	0.2398	0.3192	0.1008	0.3602	15.7057	73.4019	77.7513

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection details
1	X-RAY DIFFRACTION	1	chain 'A' and (resid 88 through 116 )
2	X-RAY DIFFRACTION	2	chain 'A' and (resid 117 through 199 )
3	X-RAY DIFFRACTION	3	chain 'A' and (resid 200 through 227 )
4	X-RAY DIFFRACTION	4	chain 'A' and (resid 228 through 253 )
5	X-RAY DIFFRACTION	5	chain 'A' and (resid 254 through 271 )
6	X-RAY DIFFRACTION	6	chain 'A' and (resid 272 through 325 )
7	X-RAY DIFFRACTION	7	chain 'A' and (resid 326 through 349 )
8	X-RAY DIFFRACTION	8	chain 'A' and (resid 350 through 375 )
9	X-RAY DIFFRACTION	9	chain 'A' and (resid 376 through 411 )
10	X-RAY DIFFRACTION	10	chain 'B' and (resid 88 through 116 )
11	X-RAY DIFFRACTION	11	chain 'B' and (resid 117 through 199 )
12	X-RAY DIFFRACTION	12	chain 'B' and (resid 200 through 227 )
13	X-RAY DIFFRACTION	13	chain 'B' and (resid 228 through 253 )
14	X-RAY DIFFRACTION	14	chain 'B' and (resid 254 through 271 )
15	X-RAY DIFFRACTION	15	chain 'B' and (resid 272 through 325 )
16	X-RAY DIFFRACTION	16	chain 'B' and (resid 326 through 349 )
17	X-RAY DIFFRACTION	17	chain 'B' and (resid 350 through 375 )
18	X-RAY DIFFRACTION	18	chain 'B' and (resid 376 through 411 )

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