PDB-5k1i: PDE4 crystal structure in complex with small molecule inhibitor

ID or keywords:

Entry

Database: PDB / ID: 5k1i

Title

PDE4 crystal structure in complex with small molecule inhibitor

Components

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

Keywords

HYDROLASE /

phosphodiesterases /

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 /

MOLECULAR REPLACEMENT / Resolution: 2.61 Å

Authors

Segarra, V. / Hernandez, B. / Ferrer-Miralles, N. / Korndoerfer, I. / Aymami, J.

Citation

Journal: J. Med. Chem. / Year: 2016
Title: Biphenyl Pyridazinone Derivatives as Inhaled PDE4 Inhibitors: Structural Biology and Structure-Activity Relationships.
Authors: Gracia, J. / Buil, M.A. / Castro, J. / Eichhorn, P. / Ferrer, M. / Gavalda, A. / Hernandez, B. / Segarra, V. / Lehner, M.D. / Moreno, I. / Pages, L. / Roberts, R.S. / Serrat, J. / Sevilla, S. ...

History

Deposition	May 18, 2016	Deposition site: RCSB / Processing site: PDBE
Revision 1.0	Dec 21, 2016	Provider: repository / Type: Initial release
Revision 1.1	Jan 10, 2024	Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id

Structure viewer	Molecule: MolmilJmol/JSmol

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Download

PDBx/mmCIF format	5k1i.cif.gz	1 MB	Display	PDBx/mmCIF format
PDB format	pdb5k1i.ent.gz	863.3 KB	Display	PDB format
PDBx/mmJSON format	5k1i.json.gz		Tree view	PDBx/mmJSON format
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Validation report

Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/k1/5k1i ftp://data.pdbj.org/pub/pdb/validation_reports/k1/5k1i	HTTPS FTP

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Related structure data

Related structure data	1tb7S S: Starting model for refinement
Similar structure data	1y2k-2 1y2k-1 1xor-2 1y2e-2 1xon-2 5wh6-1 1tb7-1 4ys7-3 5tkb-4 1xoq-1 6fet-3 3g4k-4 5tkb-3 1xlz-2 1xlx-1 1y2b-2 1xm4-1 3ly2-6 Search similar-shape structures by Omokage search (details) Search similar-shape structures by Omokage search (details) Search similar-shape structures by Omokage search (details) Search similar-shape structures by Omokage search (details) Search similar-shape structures by Omokage search (details) Search similar-shape structures by Omokage search (details) Search similar-shape structures by Omokage search (details) Search similar-shape structures by Omokage search (details) Search similar-shape structures by Omokage search (details) Similarity search - Function & homologyF&H Search Similarity search - FunctionF&H Search Similarity search - HomologyF&H Search

Related structure data

1tb7S

S: Starting model for refinement

Similar structure data

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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

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

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

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

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

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

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

hetero molecules

304 kDa, 8 polymers
Search similar-shape structures of this assembly by Omokage search (details)

1

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

hetero molecules

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

2

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

hetero molecules

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

3

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

hetero molecules

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

4

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

hetero molecules

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

5

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

hetero molecules

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

6

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

hetero molecules

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

7

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

hetero molecules

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

8

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

hetero molecules

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

Unit cell

Length a, b, c (Å)	61.444, 78.347, 161.756
Angle α, β, γ (deg.)	91.010, 92.790, 90.080
Int Tables number	1
Space group name H-M	P1

Noncrystallographic symmetry (NCS)

NCS domain:
NCS domain segments:

Dom-ID	Component-ID	Ens-ID	Refine code	Auth asym-ID	Auth seq-ID
1	1	1	4	A	86 - 292
2	1	1	4	B	86 - 292
3	1	1	4	C	86 - 292
4	1	1	4	D	86 - 292
5	1	1	4	E	86 - 292
6	1	1	4	F	86 - 292
7	1	1	4	G	86 - 292
8	1	1	4	H	86 - 292
1	1	2	4	B	293 - 296
2	1	2	4	D	293 - 296
3	1	2	4	F	293 - 296
4	1	2	4	H	293 - 296
1	1	3	4	A	297 - 411
2	1	3	4	B	297 - 411
3	1	3	4	C	297 - 411
4	1	3	4	D	297 - 411
5	1	3	4	E	297 - 411
6	1	3	4	F	297 - 411
7	1	3	4	G	297 - 411
8	1	3	4	H	297 - 411
1	2	3	4	A	1001
2	2	3	4	B	1001
3	2	3	4	C	1001
4	2	3	4	D	1001
5	2	3	4	E	1001
6	2	3	4	F	1001
7	2	3	4	G	1001
8	2	3	4	H	1001
1	3	3	4	A	2001 - 2002
2	3	3	4	B	2001 - 2002
3	3	3	4	C	2001 - 2002
4	3	3	4	D	2001 - 2002
5	3	3	4	E	2001 - 2002
6	3	3	4	F	2001 - 2002
7	3	3	4	G	2001 - 2002
8	3	3	4	H	2001 - 2002

NCS ensembles :

ID
1
2
3

#1: Protein	cAMP-specific 3',5'-cyclic phosphodiesterase 4D / DPDE3 / PDE43 Mass: 37578.594 Da / Num. of mol.: 8 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PDE4D, DPDE3 / Production host: Escherichia coli BL21(DE3) (bacteria) References: UniProt: Q08499, 3',5'-cyclic-AMP phosphodiesterase
#2: Chemical	ChemComp-6PT / 4-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]benzoic acid Mass: 377.393 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C₂₁H₁₉N₃O₄
#3: Chemical	ChemComp-ZN / ZINC ION Mass: 65.409 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Zn
#4: Chemical	ChemComp-MG / MAGNESIUM ION Mass: 24.305 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Mg
#5: Water	ChemComp-HOH / water / Water Mass: 18.015 Da / Num. of mol.: 210 / Source method: isolated from a natural source / Formula: H₂O

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Experiment

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

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Sample preparation

Crystal	Density Matthews: 2.59 Å³/Da / Density % sol: 52.45 %
Crystal grow	Temperature: 293 K / Method: vapor diffusion / pH: 7.5 Details: 19% PEG 3350, 36 % Ethylene Glycol and 10 % Isopropanol as a precipitant

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Data collection

Diffraction	Mean temperature: 293 K
Diffraction source	Source: ROTATING ANODE / Type: ENRAF-NONIUS FR571 / Wavelength: 1.54 Å
Detector	Type: MARRESEARCH / Detector: IMAGE PLATE / Date: Apr 4, 2005
Radiation	Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 1.54 Å / Relative weight: 1
Reflection	Resolution: 2.6→25 Å / Num. obs: 91922 / % possible obs: 94.6 % / Observed criterion σ(F): 7 / Redundancy: 2.6 % / R_rim(I) all: 0.126 / Net I/σ(I): 7
Reflection shell	Resolution: 2.6→2.74 Å / R_rim(I) all: 0.395

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Processing

Software

Name	Version	Classification
REFMAC	5.2.0005	refinement
PDB_EXTRACT	3.2	data extraction
MOSFLM		data reduction
SCALA		data scaling

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT
Starting model: 1TB7

1tb7

Resolution: 2.61→25 Å / Cor.coef. F_o:F_c: 0.922 / Cor.coef. F_o:F_c free: 0.857 / SU B: 24.4 / SU ML: 0.253 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.355 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS

	R_factor	Num. reflection	% reflection	Selection details
R_free	0.2583	4409	5.1 %	RANDOM
R_work	0.1913	-	-	-
obs	0.1947	82704	94.77 %	-

Solvent computation

Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å

Displacement parameters

B_iso max: 88.31 Å² / B_iso mean: 30.959 Å² / B_iso min: 2 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	-0.01 Å²	0.18 Å²	0.37 Å²
2-	-	0.15 Å²	-0.55 Å²
3-	-	-	-0.12 Å²

Refinement step

Cycle: final / Resolution: 2.61→25 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	20993	0	240	210	21443
B_iso mean	-	-	30.03	19.58	-
Num. residues	-	-	-	-	2590

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.012	0.021	21661
X-RAY DIFFRACTION	r_angle_refined_deg	1.471	1.956	29436
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	5.525	5	2578
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	35.423	25.147	1088
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	17.812	15	3816
X-RAY DIFFRACTION	r_dihedral_angle_4_deg	15.917	15	104
X-RAY DIFFRACTION	r_chiral_restr	0.1	0.2	3362
X-RAY DIFFRACTION	r_gen_planes_refined	0.005	0.02	16380
X-RAY DIFFRACTION	r_nbd_refined	0.257	0.3	11141
X-RAY DIFFRACTION	r_nbtor_refined	0.328	0.5	15207
X-RAY DIFFRACTION	r_xyhbond_nbd_refined	0.188	0.5	1534
X-RAY DIFFRACTION	r_metal_ion_refined	0.089	0.5	3
X-RAY DIFFRACTION	r_symmetry_vdw_refined	0.243	0.3	71
X-RAY DIFFRACTION	r_symmetry_hbond_refined	0.265	0.5	22
X-RAY DIFFRACTION	r_mcbond_it	0.66	2	13211
X-RAY DIFFRACTION	r_mcangle_it	1.05	3	21102
X-RAY DIFFRACTION	r_scbond_it	0.718	2	9459
X-RAY DIFFRACTION	r_scangle_it	1.087	3	8334

Refine LS restraints NCS

Dom-ID: 1 / Refine-ID: X-RAY DIFFRACTION

Ens-ID	Auth asym-ID	Number	Type	Rms dev position (Å)	Weight position
1	A	1644	MEDIUM POSITIONAL	0.32	0.5
1	B	1644	MEDIUM POSITIONAL	0.31	0.5
1	C	1644	MEDIUM POSITIONAL	0.35	0.5
1	D	1644	MEDIUM POSITIONAL	0.35	0.5
1	E	1644	MEDIUM POSITIONAL	0.34	0.5
1	F	1644	MEDIUM POSITIONAL	0.34	0.5
1	G	1644	MEDIUM POSITIONAL	0.32	0.5
1	H	1644	MEDIUM POSITIONAL	0.32	0.5
1	A	1644	MEDIUM THERMAL	0.56	2
1	B	1644	MEDIUM THERMAL	0.62	2
1	C	1644	MEDIUM THERMAL	0.61	2
1	D	1644	MEDIUM THERMAL	0.61	2
1	E	1644	MEDIUM THERMAL	0.65	2
1	F	1644	MEDIUM THERMAL	0.51	2
1	G	1644	MEDIUM THERMAL	0.62	2
1	H	1644	MEDIUM THERMAL	0.6	2
2	B	23	MEDIUM POSITIONAL	0.26	0.5
2	D	23	MEDIUM POSITIONAL	0.39	0.5
2	F	23	MEDIUM POSITIONAL	0.42	0.5
2	H	23	MEDIUM POSITIONAL	0.44	0.5
2	B	23	MEDIUM THERMAL	0.56	2
2	D	23	MEDIUM THERMAL	0.53	2
2	F	23	MEDIUM THERMAL	0.62	2
2	H	23	MEDIUM THERMAL	0.56	2
3	A	993	MEDIUM POSITIONAL	0.49	0.5
3	B	993	MEDIUM POSITIONAL	0.4	0.5
3	C	993	MEDIUM POSITIONAL	0.42	0.5
3	D	993	MEDIUM POSITIONAL	0.4	0.5
3	E	993	MEDIUM POSITIONAL	0.41	0.5
3	F	993	MEDIUM POSITIONAL	0.47	0.5
3	G	993	MEDIUM POSITIONAL	0.41	0.5
3	H	993	MEDIUM POSITIONAL	0.48	0.5
3	A	993	MEDIUM THERMAL	0.63	2
3	B	993	MEDIUM THERMAL	0.69	2
3	C	993	MEDIUM THERMAL	0.61	2
3	D	993	MEDIUM THERMAL	0.65	2
3	E	993	MEDIUM THERMAL	0.57	2
3	F	993	MEDIUM THERMAL	0.58	2
3	G	993	MEDIUM THERMAL	0.67	2
3	H	993	MEDIUM THERMAL	0.59	2

LS refinement shell

Resolution: 2.606→2.673 Å / Total num. of bins used: 20

	R_factor	Num. reflection	% reflection
R_free	0.342	294	-
R_work	0.243	5440	-
all	-	5734	-
obs	-	-	84.67 %

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	3.8263	-0.1238	-1.0079	1.169	-0.2174	2.63	-0.0798	-0.0609	-0.105	0.1805	0.0828	-0.0617	-0.2579	-0.1344	-0.003	-0.0121	0.0722	-0.0519	-0.112	0.0009	-0.1817	23.265	-0.108	66.503
2	2.4569	-0.4544	-0.1482	1.8329	0.7719	1.9833	0.0077	-0.0213	-0.0485	0.0005	0.0094	0.0997	0.0517	0.1444	-0.0171	-0.1871	-0.0366	-0.0019	-0.1863	0.0626	-0.1967	15.031	3.251	27.229
3	1.1437	-0.1087	-0.0199	1.5357	-0.473	2.062	-0.0175	0.0268	0.0002	-0.1117	0.0254	-0.0318	-0.0718	-0.0415	-0.0079	-0.1429	-0.0355	-0.0113	-0.1419	0.0034	-0.22	7.884	71.731	107.528
4	2.0031	-0.2581	0.6576	0.9656	0.1216	2.0157	-0.093	-0.1016	0.0866	0.0772	0.0404	0.0699	-0.154	-0.1085	0.0526	-0.1172	-0.0115	0.0075	-0.1933	0.0618	-0.1845	-3.96	73.594	146.08
5	0.7355	0.3168	0.126	1.8175	0.6864	1.9912	-0.0131	0.0635	-0.0002	0.0062	0.0168	0.0811	-0.0683	0.1131	-0.0036	-0.1683	-0.0164	-0.0165	-0.1715	0.0561	-0.2184	38.187	33.185	134.194
6	2.0672	0.1607	0.3355	1.7122	-0.3553	2.6912	-0.0976	0.1485	0.1082	-0.3209	0.0467	-0.0459	0.3053	-0.1881	0.0509	0.029	-0.1452	0.0285	-0.0704	-0.0208	-0.1779	46.85	36.233	95.015
7	1.6265	0.4009	-0.7136	1.049	0.0864	2.5876	-0.0829	0.0849	-0.0893	-0.0874	0.0264	0.0575	0.1641	-0.1002	0.0565	-0.1244	-0.0369	-0.0096	-0.2028	0.054	-0.182	34.691	41.395	15.439
8	1.6589	0.5448	-0.2728	1.9804	-0.2908	2.2311	-0.0235	-0.0806	-0.018	0.2112	0.0651	-0.0645	0.0914	0.1013	-0.0416	-0.115	0.0119	0.0097	-0.1401	0.0005	-0.201	46.455	42.962	53.969

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Auth asym-ID	Auth seq-ID
1	X-RAY DIFFRACTION	1	A	87 - 292
2	X-RAY DIFFRACTION	1	A	297 - 411
3	X-RAY DIFFRACTION	2	B	86 - 411
4	X-RAY DIFFRACTION	3	C	87 - 292
5	X-RAY DIFFRACTION	3	C	297 - 411
6	X-RAY DIFFRACTION	4	D	86 - 411
7	X-RAY DIFFRACTION	5	E	87 - 292
8	X-RAY DIFFRACTION	5	E	297 - 411
9	X-RAY DIFFRACTION	6	F	86 - 411
10	X-RAY DIFFRACTION	7	G	87 - 292
11	X-RAY DIFFRACTION	7	G	297 - 411
12	X-RAY DIFFRACTION	8	H	86 - 411

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