PDB-8k4h: Crystal structure of PDE4D complexed with benzbromarone

ID or keywords:

Entry

Database: PDB / ID: 8k4h

Title

Crystal structure of PDE4D complexed with benzbromarone

Components

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

Keywords

HYDROLASE /

PDE4D /

Complex /

Benzbromarone / Inhibitor

Function / homology

Function and homology information

signaling receptor regulator activity / negative regulation of relaxation of cardiac muscle / negative regulation of heart contraction /

3',5'-cyclic-AMP phosphodiesterase / positive regulation of interleukin-5 production / regulation of cardiac muscle cell contraction / establishment of endothelial barrier / negative regulation of cAMP-mediated signaling /

beta-2 adrenergic receptor binding / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 1.95 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	Jul 18, 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	8k4h.cif.gz	278.4 KB	Display	PDBx/mmCIF format
PDB format	pdb8k4h.ent.gz	222.8 KB	Display	PDB format
PDBx/mmJSON format	8k4h.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/k4/8k4h ftp://data.pdbj.org/pub/pdb/validation_reports/k4/8k4h	HTTPS FTP

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Related structure data

Related structure data	8k4cC 8w4qC 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

81.3 kDa, 2 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)	57.507, 79.808, 162.270
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, 141 molecules

#2: Chemical	ChemComp-ZN / ZINC ION Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical	ChemComp-MG / MAGNESIUM ION Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical	ChemComp-R75 / [3,5-bis(bromanyl)-4-oxidanyl-phenyl]-(2-ethyl-1-benzofuran-3-yl)methanone / Benzbromarone / Benzbromarone Mass: 424.083 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C₁₇H₁₂Br₂O₃ / Feature type: SUBJECT OF INVESTIGATION / Comment: antiarrhythmic, inhibitor*YM
#5: Chemical	ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₂H₆O₂
#6: Water	ChemComp-HOH / water / Water Mass: 18.015 Da / Num. of mol.: 133 / 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: 2.32 Å³/Da / Density % sol: 47.02 %
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) PEG 3350

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Data collection

Diffraction

Mean temperature: 100 K / Serial crystal experiment: N

Diffraction source

Source:

SYNCHROTRON / Site:

SSRF

/ Beamline: BL18U1 / Wavelength: 0.979 Å

Detector

Type: ADSC QUANTUM 315 / Detector: CCD / Date: Mar 20, 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: 1.95→50 Å / Num. obs: 55562 / % possible obs: 100 % / Redundancy: 13 % / CC_1/2: 0.984 / CC star: 0.996 / R_merge(I) obs: 0.162 / R_pim(I) all: 0.047 / R_rim(I) all: 0.169 / Χ²: 0.582 / Net I/σ(I): 2.8 / Num. measured all: 724179

Reflection shell

Diffraction-ID: 1 / % possible all: 100

Resolution (Å)	Redundancy (%)	R_merge(I) obs	Num. unique obs	CC_1/2	CC star	R_pim(I) all	R_rim(I) all	Χ²
1.95-2.02	13.4	0.927	5454	0.872	0.965	0.262	0.963	0.44
2.02-2.1	12.9	0.689	5498	0.93	0.982	0.199	0.717	0.459
2.1-2.2	13.1	0.51	5467	0.95	0.987	0.146	0.531	0.486
2.2-2.31	12.9	0.418	5486	0.964	0.991	0.121	0.436	0.527
2.31-2.46	13.6	0.318	5504	0.977	0.994	0.09	0.331	0.536
2.46-2.65	13.2	0.252	5522	0.985	0.996	0.072	0.262	0.546
2.65-2.91	13.1	0.191	5541	0.989	0.997	0.055	0.198	0.582
2.91-3.33	13.3	0.141	5573	0.993	0.998	0.04	0.147	0.661
3.33-4.2	12.9	0.103	5626	0.995	0.999	0.03	0.107	0.793
4.2-50	12.1	0.087	5891	0.996	0.999	0.026	0.091	0.79

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Processing

Software

Name	Version	Classification
PHENIX	(1.17.1_3660)	refinement
HKL-3000		data scaling
HKL-3000		data reduction
PHASER		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT / Resolution: 1.95→40.45 Å / SU ML: 0.25 / Cross valid method: THROUGHOUT / σ(F): 1.38 / Phase error: 27.89 / Stereochemistry target values: ML

	R_factor	Num. reflection	% reflection
R_free	0.2789	2883	5.2 %
R_work	0.2468	-	-
obs	0.2484	55462	99.66 %

Solvent computation

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

Refinement step

Cycle: LAST / Resolution: 1.95→40.45 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	5137	0	56	133	5326

Refine LS restraints

Refine-ID	Type	Dev ideal	Number
X-RAY DIFFRACTION	f_bond_d	0.003	5299
X-RAY DIFFRACTION	f_angle_d	0.526	7229
X-RAY DIFFRACTION	f_dihedral_angle_d	15.268	1905
X-RAY DIFFRACTION	f_chiral_restr	0.036	843
X-RAY DIFFRACTION	f_plane_restr	0.004	931

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 (%)
1.95-1.98	0.3488	120	0.2796	2349	X-RAY DIFFRACTION	94
1.98-2.01	0.2993	143	0.2671	2445	X-RAY DIFFRACTION	100
2.01-2.05	0.3062	137	0.2669	2500	X-RAY DIFFRACTION	100
2.05-2.09	0.3196	137	0.2622	2446	X-RAY DIFFRACTION	100
2.09-2.13	0.3228	154	0.2613	2476	X-RAY DIFFRACTION	100
2.13-2.18	0.3304	145	0.2466	2442	X-RAY DIFFRACTION	100
2.18-2.23	0.2835	135	0.2468	2496	X-RAY DIFFRACTION	100
2.23-2.28	0.301	148	0.2556	2485	X-RAY DIFFRACTION	100
2.28-2.35	0.299	132	0.2473	2494	X-RAY DIFFRACTION	100
2.35-2.41	0.287	142	0.242	2479	X-RAY DIFFRACTION	100
2.41-2.49	0.2517	129	0.2476	2506	X-RAY DIFFRACTION	100
2.49-2.58	0.2791	118	0.253	2512	X-RAY DIFFRACTION	100
2.58-2.68	0.2899	123	0.2496	2496	X-RAY DIFFRACTION	100
2.68-2.81	0.3188	137	0.2471	2510	X-RAY DIFFRACTION	100
2.81-2.95	0.2679	143	0.2481	2500	X-RAY DIFFRACTION	100
2.95-3.14	0.2719	149	0.2526	2494	X-RAY DIFFRACTION	100
3.14-3.38	0.2885	139	0.2465	2554	X-RAY DIFFRACTION	100
3.38-3.72	0.2645	147	0.2426	2501	X-RAY DIFFRACTION	100
3.72-4.26	0.2684	143	0.2289	2572	X-RAY DIFFRACTION	100
4.26-5.37	0.2353	125	0.2239	2604	X-RAY DIFFRACTION	100
5.37-40.45	0.2726	137	0.266	2718	X-RAY DIFFRACTION	100

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	3.1913	1.1922	0.0417	2.5456	-0.1073	2.0975	0.0917	0.3484	0.2768	-0.5994	-0.0013	0.2811	-0.4364	-0.2578	-0.0615	0.5513	0.1331	0.0195	0.4538	0.0773	0.3217	10.7285	12.4264	12.7378
2	0.4612	-0.0603	-0.1095	0.8927	0.3233	1.0604	0.1055	0.0834	0.1156	-0.2323	-0.0928	0.1194	-0.3124	-0.2908	0.004	0.2817	0.088	0.0061	0.2543	0.0116	0.2635	8.0796	11.232	27.1203
3	0.2514	-0.0649	-0.2287	0.2722	-0.2648	1.0421	-0.085	0.0486	0.072	-0.0343	0.1213	-0.2357	-0.0428	0.396	-0.0413	0.2314	0.0073	0.0289	0.3376	-0.0373	0.3224	28.9115	5.9421	38.6402
4	2.5734	-1.2371	-0.0242	1.1748	-0.0519	0.6613	0.0244	-0.025	0.1541	0.0711	-0.0046	-0.0313	-0.3448	-0.0402	0.0041	0.2663	0.0172	0.0765	0.2159	-0.0097	0.2881	12.7656	16.7032	37.9083
5	4.5206	-2.0138	-0.7472	2.7443	0.5359	1.8399	-0.0599	-0.1753	0.1646	0.2008	0.0227	0.0798	-0.0993	-0.2966	-0.0001	0.2171	-0.0284	0.0196	0.2798	0.0529	0.2379	7.5444	7.6108	41.3781
6	0.4564	0.0168	-0.3996	0.9117	-0.0347	1.0325	-0.1811	-0.0222	-0.1026	0.0855	-0.0348	0.2162	0.3006	-0.3013	0.0871	0.2239	-0.0428	0.0206	0.2465	-0.011	0.2845	7.2853	-7.0759	33.0967
7	2.4256	0.0058	1.1899	1.2241	0.0856	2.3084	0.0742	-0.0088	0.1252	-0.2886	0.009	-0.2312	-0.1464	0.5247	0.0114	0.3379	0.0062	0.146	0.3393	-0.0189	0.3607	30.0481	1.6924	20.596
8	1.1651	0.7086	0.8297	0.7628	0.6387	0.6479	-0.0013	-0.088	-0.1008	-0.0625	0.1975	-0.3546	0.365	0.5397	-0.0843	0.3029	0.0854	0.0472	0.4162	-0.0158	0.4239	33.0232	-6.8732	23.7628
9	0.5399	0.0238	-0.1845	1.2048	-0.0614	1.9193	-0.1078	0.188	-0.2657	0.0094	-0.1166	0.0849	0.4869	-0.2206	0.1626	0.4338	-0.0531	0.0295	0.2749	-0.0308	0.3759	13.2709	-11.4248	18.7192
10	1.218	-0.6966	-0.2854	0.7376	-0.247	1.2905	-0.5791	-0.2609	0.5132	-0.2972	0.7932	0.2845	0.2919	0.7711	-0.0559	0.1132	0.4746	0.1708	0.6837	-0.3968	0.027	31.7962	5.7686	66.1597
11	1.8914	0.1038	-0.2776	1.7621	0.3351	1.1386	-0.3982	-0.0862	-0.0035	0.209	0.3582	-0.1081	0.7001	0.465	0.061	0.5897	0.1896	0.0393	0.4401	-0.0896	0.3069	28.7026	-3.3826	56.9955
12	0.6282	0.1463	-0.9174	0.3663	0.2537	1.2954	-0.1049	-0.1513	0.0919	-0.1546	0.0437	-0.012	0.598	0.1213	0.0665	0.7573	0.236	0.0411	0.4678	-0.0081	0.3293	14.8954	2.3864	72.3688

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection details
1	X-RAY DIFFRACTION	1	chain 'A' and (resid 86 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 86 through 227 )
11	X-RAY DIFFRACTION	11	chain 'B' and (resid 228 through 302 )
12	X-RAY DIFFRACTION	12	chain 'B' and (resid 303 through 411 )

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