PDB-4z83: PKAB3 in complex with pyrrolidine inhibitor 47a

ID or keywords:

Entry

Database: PDB / ID: 4z83

Title

PKAB3 in complex with pyrrolidine inhibitor 47a

Components

cAMP-dependent protein kinase catalytic subunit alpha
cAMP-dependent protein kinase inhibitor alpha

Keywords

TRANSFERASE / inhibitor / protein kinase / structure-guided

Function / homology

Function and homology information

CD209 (DC-SIGN) signaling / HDL assembly / Regulation of insulin secretion / Rap1 signalling / Ion homeostasis / PKA activation in glucagon signalling / DARPP-32 events / CREB1 phosphorylation through the activation of Adenylate Cyclase / GPER1 signaling / Factors involved in megakaryocyte development and platelet production ...CD209 (DC-SIGN) signaling / HDL assembly / Regulation of insulin secretion / Rap1 signalling / Ion homeostasis / PKA activation in glucagon signalling / DARPP-32 events / CREB1 phosphorylation through the activation of Adenylate Cyclase / GPER1 signaling / Factors involved in megakaryocyte development and platelet production / Loss of Nlp from mitotic centrosomes / Recruitment of mitotic centrosome proteins and complexes / Loss of proteins required for interphase microtubule organization from the centrosome / Anchoring of the basal body to the plasma membrane / RET signaling / AURKA Activation by TPX2 / Interleukin-3, Interleukin-5 and GM-CSF signaling / Recruitment of NuMA to mitotic centrosomes / VEGFA-VEGFR2 Pathway / negative regulation of cAMP-dependent protein kinase activity / negative regulation of cAMP/PKA signal transduction / PKA activation / MAPK6/MAPK4 signaling / GLI3 is processed to GLI3R by the proteasome / Regulation of PLK1 Activity at G2/M Transition / Hedgehog 'off' state / cAMP-dependent protein kinase inhibitor activity / cAMP-dependent protein kinase / cAMP-dependent protein kinase activity / cAMP-dependent protein kinase complex / AMP-activated protein kinase activity / negative regulation of protein import into nucleus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Mitochondrial protein degradation / protein kinase A regulatory subunit binding / protein kinase A catalytic subunit binding / mesoderm formation / sperm flagellum / negative regulation of TORC1 signaling / regulation of G2/M transition of mitotic cell cycle / protein kinase A signaling / acrosomal vesicle / neuromuscular junction / cellular response to heat / peptidyl-serine phosphorylation / protein kinase activity / protein phosphorylation / protein domain specific binding / protein serine kinase activity / protein serine/threonine kinase activity / perinuclear region of cytoplasm / negative regulation of transcription by RNA polymerase II / mitochondrion / ATP binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function

Biological species

Bos taurus (cattle)

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 1.8 Å

Authors

Lund, B.A. / Alam, K.A. / Engh, R.A.

Citation

Journal: Chemistry / Year: 2016
Title: Addressing the Glycine-Rich Loop of Protein Kinases by a Multi-Facetted Interaction Network: Inhibition of PKA and a PKB Mimic.
Authors: Lauber, B.S. / Hardegger, L.A. / Asraful, A.K. / Lund, B.A. / Dumele, O. / Harder, M. / Kuhn, B. / Engh, R.A. / Diederich, F.

History

Deposition	Apr 8, 2015	Deposition site: RCSB / Processing site: PDBE
Revision 1.0	Dec 2, 2015	Provider: repository / Type: Initial release
Revision 1.1	Jan 27, 2016	Group: Database references
Revision 1.2	Jan 10, 2024	Group: Data collection / Database references / Refinement description Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

Structure viewer	Molecule: MolmilJmol/JSmol

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PDBx/mmCIF format	4z83.cif.gz	230.4 KB	Display	PDBx/mmCIF format
PDB format	pdb4z83.ent.gz	186.2 KB	Display	PDB format
PDBx/mmJSON format	4z83.json.gz		Tree view	PDBx/mmJSON format
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Validation report

Summary document	4z83_validation.pdf.gz	995.3 KB	Display	wwPDB validaton report
Full document	4z83_full_validation.pdf.gz	996.4 KB	Display
Data in XML	4z83_validation.xml.gz	19.3 KB	Display
Data in CIF	4z83_validation.cif.gz	28.8 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/z8/4z83 ftp://data.pdbj.org/pub/pdb/validation_reports/z8/4z83	HTTPS FTP

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Related structure data

Related structure data	4uj1C 4uj2C 4uj9C 4ujaC 4ujbC 4z84C 1rdqS 1q61 S: Starting model for refinement C: citing same article (ref.)
Similar structure data	3owp-d 2gnj-d 4uja-d 2uw4-d 2vnw-d 4uj1-d 3zo3-d 3zo4-d 2c1a-d 5k78-3 2jds-d Search similar-shape structures by Omokage search (details) 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) #251 - Nov 2020 Adenylyl Cyclase similarity (1) #183 - Mar 2015 Phototropin similarity (7) #196 - Apr 2016 Lead Poisoning similarity (3)

Deposited unit

E: cAMP-dependent protein kinase catalytic subunit alpha

I: cAMP-dependent protein kinase inhibitor alpha

hetero molecules

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

1

Idetical with deposited unit
defined by software

Unit cell

Length a, b, c (Å)	82.575, 61.491, 78.948
Angle α, β, γ (deg.)	90.00, 90.00, 90.00
Int Tables number	19
Space group name H-M	P2₁2₁2₁

#1: Protein	cAMP-dependent protein kinase catalytic subunit alpha / PKA C-alpha Mass: 40697.449 Da / Num. of mol.: 1 / Mutation: V123A, L173M, Q181K Source method: isolated from a genetically manipulated source Source: (gene. exp.) Bos taurus (cattle) / Gene: PRKACA / Plasmid: pT7-7 / Production host: Escherichia coli (E. coli) / References: UniProt: P00517, cAMP-dependent protein kinase
#2: Protein/peptide	cAMP-dependent protein kinase inhibitor alpha / PKI-alpha / cAMP-dependent protein kinase inhibitor / muscle/brain isoform Mass: 2226.411 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P61925
#3: Chemical	ChemComp-4L7 / 7-{(3S,4R)-4-[(5-bromothiophen-2-yl)carbonyl]pyrrolidin-3-yl}quinazolin-4(3H)-one Mass: 404.281 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₁₇H₁₄BrN₃O₂S
#4: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 375 / Source method: isolated from a natural source / Formula: H₂O

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Experiment

Experiment	Method: X-RAY DIFFRACTION

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Sample preparation

Crystal	Density Matthews: 2.33 Å³/Da / Density % sol: 47.28 %
Crystal grow	Temperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7 Details: The droplets, containing 16 mg/ml PKAB3, 25 mM Bis-Tris-HCl, pH 7.0, 150 mM KCl, 1.5mM octanoyl-N-methylglucamide and 0.8 mM PKI peptide, were equilibrated against 12-26 % (v/v) methanol.

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Data collection

Diffraction	Mean temperature: 100 K
Diffraction source	Source: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.91841 Å
Detector	Type: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Nov 24, 2012
Radiation	Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 0.91841 Å / Relative weight: 1
Reflection	Resolution: 1.8→35.614 Å / Num. obs: 37443 / % possible obs: 98.6 % / Redundancy: 3.9 % / R_merge(I) obs: 0.08579 / Net I/σ(I): 10.78
Reflection shell	Resolution: 1.8→1.8232 Å / % possible all: 0.85

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Processing

Software

Name	Version	Classification
PHENIX	1.8.4_1496	refinement
XDS	November 11, 2013	data reduction
PHASER	2.5.5	phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT
Starting model: 1rdq

1rdq

Resolution: 1.8→35.614 Å / SU ML: 0.25 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 22.09 / Stereochemistry target values: ML

	R_factor	Num. reflection	% reflection
R_free	0.2175	3620	5.25 %
R_work	0.1798	-	-
obs	0.1818	68972	95.76 %

Solvent computation

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

Refinement step

Cycle: LAST / Resolution: 1.8→35.614 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	2885	0	33	375	3293

Refine LS restraints

Refine-ID	Type	Dev ideal	Number
X-RAY DIFFRACTION	f_bond_d	0.026	2996
X-RAY DIFFRACTION	f_angle_d	1.013	4055
X-RAY DIFFRACTION	f_dihedral_angle_d	12.336	1113
X-RAY DIFFRACTION	f_chiral_restr	0.038	426
X-RAY DIFFRACTION	f_plane_restr	0.007	545

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 (%)
1.7995-1.8232	0.3792	129	0.3203	2248	X-RAY DIFFRACTION	85
1.8232-1.8482	0.3354	133	0.3552	2580	X-RAY DIFFRACTION	99
1.8482-1.8746	0.385	155	0.3274	2637	X-RAY DIFFRACTION	99
1.8746-1.9026	0.3153	126	0.333	2534	X-RAY DIFFRACTION	98
1.9026-1.9323	0.346	138	0.3175	2402	X-RAY DIFFRACTION	91
1.9323-1.964	0.3373	153	0.2897	2554	X-RAY DIFFRACTION	98
1.964-1.9978	0.2901	131	0.2455	2640	X-RAY DIFFRACTION	100
1.9978-2.0342	0.2484	159	0.2243	2575	X-RAY DIFFRACTION	100
2.0342-2.0733	0.2481	137	0.224	2568	X-RAY DIFFRACTION	98
2.0733-2.1156	0.2923	123	0.2026	2683	X-RAY DIFFRACTION	99
2.1156-2.1616	0.2201	149	0.1928	2554	X-RAY DIFFRACTION	100
2.1616-2.2119	0.2053	141	0.2135	2561	X-RAY DIFFRACTION	98
2.2119-2.2672	0.2809	128	0.2054	2338	X-RAY DIFFRACTION	89
2.2672-2.3285	0.2173	144	0.1726	2631	X-RAY DIFFRACTION	99
2.3285-2.397	0.2056	154	0.1689	2590	X-RAY DIFFRACTION	99
2.397-2.4743	0.2015	139	0.164	2598	X-RAY DIFFRACTION	99
2.4743-2.5627	0.2115	149	0.1635	2576	X-RAY DIFFRACTION	99
2.5627-2.6653	0.2357	150	0.1699	2565	X-RAY DIFFRACTION	98
2.6653-2.7866	0.2244	148	0.176	2577	X-RAY DIFFRACTION	98
2.7866-2.9334	0.2157	140	0.1664	2558	X-RAY DIFFRACTION	97
2.9334-3.1171	0.2004	143	0.1633	2503	X-RAY DIFFRACTION	96
3.1171-3.3576	0.1923	122	0.1591	2500	X-RAY DIFFRACTION	95
3.3576-3.6952	0.2054	131	0.155	2424	X-RAY DIFFRACTION	92
3.6952-4.2291	0.1688	138	0.1351	2335	X-RAY DIFFRACTION	90
4.2291-5.3254	0.1468	129	0.1347	2344	X-RAY DIFFRACTION	89
5.3254-35.6209	0.2244	131	0.1786	2277	X-RAY DIFFRACTION	87

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	1.2457	-0.2918	-0.6978	1.4513	0.848	1.8309	-0.1966	-0.0495	-0.2463	-0.1362	0.0391	-0.3332	0.3644	0.3978	0.0519	0.2131	0.0685	0.0222	0.2928	0.0227	0.2841	-3.7919	-12.7561	-5.1847
2	2.1755	0.0054	0.4094	1.6852	0.1407	1.9073	-0.073	-0.2365	-0.5118	0.3226	0.0822	-0.1727	0.7837	0.2775	0.0268	0.4073	0.1272	0.0388	0.2625	0.0689	0.3448	-9.1991	-20.4054	4.1462
3	0.7145	-0.0738	-0.2058	1.2266	0.5721	1.4816	-0.0744	-0.0671	-0.0922	0.0495	-0.0027	-0.106	0.1591	0.2499	0.0682	0.1861	0.016	-0.0021	0.2342	0.0424	0.2056	-8.5478	-4.5896	1.9666
4	2.3224	-0.1823	0.0715	1.7088	0.466	2.0169	0.0003	0.1087	-0.0381	-0.1138	-0.0983	-0.0539	0.0239	0.0975	0.1224	0.2535	-0.021	-0.0013	0.1981	0.0157	0.1891	-15.3184	-2.3949	-7.921
5	1.7734	0.6883	-0.1474	2.3558	1.3513	2.997	-0.0128	0.0157	-0.0162	-0.0258	-0.0062	0.118	-0.0503	-0.1069	0.0202	0.1502	0.0087	-0.0275	0.154	0.0257	0.1783	-19.7058	6.6594	-0.9401
6	3.2681	0.2146	0.3586	3.0009	0.7013	4.4513	-0.0555	-0.1076	-0.1006	0.1559	-0.135	0.5691	0.0911	-0.9422	0.1532	0.2063	-0.0086	0.0237	0.3506	-0.0365	0.2786	-28.8789	7.5353	6.6205
7	3.1181	-0.3094	0.0639	2.6854	0.5868	4.3655	-0.0454	0.0458	0.2949	-0.1175	-0.1053	0.1822	-0.5385	-0.16	0.0876	0.2527	-0.0004	-0.0284	0.1848	-0.008	0.2825	-17.7724	18.5321	3.9825
8	2.7869	-0.3728	-0.6793	2.5061	0.8086	1.2041	-0.0236	0.0239	0.3761	-0.2188	0.0182	-0.4088	-0.343	0.3397	-0.0545	0.2155	-0.078	0.0085	0.2662	0.0371	0.2757	-3.8066	14.6753	-1.3402
9	1.0443	0.6047	-0.5553	1.8046	0.2842	0.5473	0.0878	-0.4723	-0.1898	0.9119	-0.1075	-0.6815	0.136	0.6756	0.1838	0.3934	0.0446	-0.1106	0.5333	0.0559	0.3772	-0.105	-3.9528	15.606
10	0.4618	0.1445	0.1539	2.7186	1.1943	0.9279	-0.1623	-0.0645	-0.3729	0.2252	-0.1964	0.315	0.644	-0.1822	0.3317	0.4635	0.006	0.1315	0.2558	0.0273	0.4527	-17.1206	-24.3874	-0.1482
11	2.1036	-0.3335	0.0576	5.5062	1.4945	3.2319	-0.16	0.0821	0.2116	0.4523	0.0773	-0.245	-0.1044	0.0048	0.0544	0.2898	-0.014	-0.0193	0.266	0.0278	0.1853	-25.7089	8.2256	19.49
12	3.6232	-1.4438	-0.8755	2.7319	-1.1727	3.0591	0.0908	0.2876	-0.3231	-0.3753	0.0147	0.1965	0.4069	-0.3609	0.032	0.3386	-0.0513	-0.0155	0.2945	0.0012	0.2462	-24.5927	-3.4436	7.6144

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection details
1	X-RAY DIFFRACTION	1	chain 'E' and (resid 14 through 54 )
2	X-RAY DIFFRACTION	2	chain 'E' and (resid 55 through 81 )
3	X-RAY DIFFRACTION	3	chain 'E' and (resid 82 through 179 )
4	X-RAY DIFFRACTION	4	chain 'E' and (resid 180 through 198 )
5	X-RAY DIFFRACTION	5	chain 'E' and (resid 199 through 233 )
6	X-RAY DIFFRACTION	6	chain 'E' and (resid 234 through 252 )
7	X-RAY DIFFRACTION	7	chain 'E' and (resid 253 through 279 )
8	X-RAY DIFFRACTION	8	chain 'E' and (resid 280 through 307 )
9	X-RAY DIFFRACTION	9	chain 'E' and (resid 308 through 327 )
10	X-RAY DIFFRACTION	10	chain 'E' and (resid 328 through 350 )
11	X-RAY DIFFRACTION	11	chain 'I' and (resid 1 through 8 )
12	X-RAY DIFFRACTION	12	chain 'I' and (resid 9 through 20 )

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