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- PDB-4uj1: Protein Kinase A in complex with an Inhibitor -

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Basic information

Entry
Database: PDB / ID: 4uj1
TitleProtein Kinase A in complex with an Inhibitor
Components
  • CAMP-DEPENDENT PROTEIN KINASE CATALYTIC SUBUNIT ALPHA
  • CAMP-DEPENDENT PROTEIN KINASE INHIBITOR ALPHA
KeywordsTRANSFERASE/INHIBITOR / TRANSFERASE-INHIBITOR COMPLEX / PROTEIN KINASE A
Function / homology
Function and homology information


cAMP/PKA signal transduction / PKA-mediated phosphorylation of CREB / PKA-mediated phosphorylation of key metabolic factors / ROBO receptors bind AKAP5 / channel activator activity / HDL assembly / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism / mitochondrial protein catabolic process / negative regulation of cAMP-dependent protein kinase activity / negative regulation of cAMP/PKA signal transduction ...cAMP/PKA signal transduction / PKA-mediated phosphorylation of CREB / PKA-mediated phosphorylation of key metabolic factors / ROBO receptors bind AKAP5 / channel activator activity / HDL assembly / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism / mitochondrial protein catabolic process / negative regulation of cAMP-dependent protein kinase activity / negative regulation of cAMP/PKA signal transduction / nucleotide-activated protein kinase complex / cell communication by electrical coupling involved in cardiac conduction / high-density lipoprotein particle assembly / Rap1 signalling / regulation of protein processing / protein localization to lipid droplet / regulation of bicellular tight junction assembly / cellular response to parathyroid hormone stimulus / regulation of osteoblast differentiation / cAMP-dependent protein kinase inhibitor activity / cAMP-dependent protein kinase / cellular response to cold / cAMP-dependent protein kinase activity / Loss of phosphorylation of MECP2 at T308 / sperm capacitation / CREB1 phosphorylation through the activation of Adenylate Cyclase / PKA activation / cAMP-dependent protein kinase complex / negative regulation of glycolytic process through fructose-6-phosphate / ciliary base / AMP-activated protein kinase activity / negative regulation of protein import into nucleus / negative regulation of interleukin-2 production / postsynaptic modulation of chemical synaptic transmission / Triglyceride catabolism / protein kinase A regulatory subunit binding / plasma membrane raft / protein kinase A catalytic subunit binding / PKA activation in glucagon signalling / Regulation of MECP2 expression and activity / mesoderm formation / RET signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / DARPP-32 events / regulation of cardiac muscle contraction / regulation of cardiac conduction / sperm flagellum / regulation of macroautophagy / renal water homeostasis / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / Hedgehog 'off' state / regulation of proteasomal protein catabolic process / negative regulation of smoothened signaling pathway / Ion homeostasis / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / positive regulation of gluconeogenesis / sperm midpiece / negative regulation of TORC1 signaling / Recruitment of NuMA to mitotic centrosomes / cellular response to glucagon stimulus / regulation of G2/M transition of mitotic cell cycle / Anchoring of the basal body to the plasma membrane / calcium channel complex / Mitochondrial protein degradation / cellular response to epinephrine stimulus / protein kinase A signaling / protein serine/threonine/tyrosine kinase activity / protein export from nucleus / CD209 (DC-SIGN) signaling / positive regulation of calcium-mediated signaling / regulation of heart rate / AURKA Activation by TPX2 / FCGR3A-mediated IL10 synthesis / acrosomal vesicle / positive regulation of protein export from nucleus / neural tube closure / Regulation of insulin secretion / cellular response to glucose stimulus / Degradation of GLI1 by the proteasome / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / MAPK6/MAPK4 signaling / neuromuscular junction / positive regulation of insulin secretion / adenylate cyclase-activating G protein-coupled receptor signaling pathway / cytokine-mediated signaling pathway / VEGFA-VEGFR2 Pathway / Vasopressin regulates renal water homeostasis via Aquaporins / mRNA processing / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / GPER1 signaling / Regulation of PLK1 Activity at G2/M Transition / manganese ion binding / Factors involved in megakaryocyte development and platelet production / cellular response to heat / peptidyl-serine phosphorylation / dendritic spine
Similarity search - Function
cAMP-dependent protein kinase inhibitor / cAMP-dependent protein kinase inhibitor / cAMP-dependent protein kinase catalytic subunit / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 ...cAMP-dependent protein kinase inhibitor / cAMP-dependent protein kinase inhibitor / cAMP-dependent protein kinase catalytic subunit / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-NVX / cAMP-dependent protein kinase catalytic subunit alpha / cAMP-dependent protein kinase inhibitor alpha
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.768 Å
AuthorsAlam, K.A. / Engh, R.A.
CitationJournal: 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
DepositionApr 7, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 13, 2016Provider: repository / Type: Initial release
Revision 1.1Jan 30, 2019Group: Data collection / Experimental preparation / Other
Category: exptl_crystal_grow / pdbx_database_proc / pdbx_database_status
Item: _exptl_crystal_grow.method / _pdbx_database_status.recvd_author_approval
Revision 1.2Feb 6, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.temp
Revision 1.3Jan 10, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_conn.pdbx_leaving_atom_flag / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: CAMP-DEPENDENT PROTEIN KINASE CATALYTIC SUBUNIT ALPHA
B: CAMP-DEPENDENT PROTEIN KINASE INHIBITOR ALPHA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,5074
Polymers43,0352
Non-polymers4722
Water6,431357
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2380 Å2
ΔGint-12.8 kcal/mol
Surface area16070 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.356, 75.409, 80.232
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein CAMP-DEPENDENT PROTEIN KINASE CATALYTIC SUBUNIT ALPHA / PKA C-ALPHA


Mass: 40808.570 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P17612, 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 / Fragment: UNP RESIDUES 6-25 / Source method: obtained synthetically / Source: (synth.) HOMO SAPIENS (human) / References: UniProt: P61925
#3: Chemical ChemComp-NVX / 7-[(3S,4R)-4-(3-chlorophenyl)carbonylpyrrolidin-3-yl]-3H-quinazolin-4-one


Mass: 353.802 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H16ClN3O2
#4: Chemical ChemComp-MPD / (4S)-2-METHYL-2,4-PENTANEDIOL


Mass: 118.174 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O2 / Comment: precipitant*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 357 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.55 Å3/Da / Density % sol: 51.81 % / Description: NONE
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 10MG/ML PROTEIN, 25MM BISTRIS/MES PH6.9, 50MM KCL, 1.5MM OCTANOYL-N-METHYLGLUCAMIDE, 1MM PROTEIN KINASE INHIBITOR PEPTIDE, VAPOR DIFFUSION, HANGING DROP, TEMPERATURE 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184
DetectorType: MARRESEARCH / Detector: CCD / Date: Oct 19, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.77→40.12 Å / Num. obs: 42975 / % possible obs: 98.6 % / Observed criterion σ(I): 2 / Redundancy: 12.9 % / Biso Wilson estimate: 23.31 Å2 / Rmerge(I) obs: 0.1 / Net I/σ(I): 19.48
Reflection shellResolution: 1.77→1.83 Å / Redundancy: 10.1 % / % possible all: 87.2

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Processing

Software
NameVersionClassification
PHENIX(PHENIX.REFINE)refinement
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3VQH

3vqh


Resolution: 1.768→40.116 Å / SU ML: 0.18 / σ(F): 1.36 / Phase error: 20.27 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2014 2149 5 %
Rwork0.1665 --
obs0.1682 42971 98.54 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.768→40.116 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2937 0 33 357 3327
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.023047
X-RAY DIFFRACTIONf_angle_d1.7594116
X-RAY DIFFRACTIONf_dihedral_angle_d15.5051143
X-RAY DIFFRACTIONf_chiral_restr0.162430
X-RAY DIFFRACTIONf_plane_restr0.009522
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7682-1.80930.26631190.24872269X-RAY DIFFRACTION83
1.8093-1.85450.29071390.23352642X-RAY DIFFRACTION97
1.8545-1.90470.29351420.21122687X-RAY DIFFRACTION99
1.9047-1.96070.21891430.20932716X-RAY DIFFRACTION100
1.9607-2.0240.2721420.19252703X-RAY DIFFRACTION100
2.024-2.09630.21221440.17452743X-RAY DIFFRACTION100
2.0963-2.18030.21031440.16272725X-RAY DIFFRACTION100
2.1803-2.27950.21621440.15962746X-RAY DIFFRACTION100
2.2795-2.39960.22011450.15742748X-RAY DIFFRACTION100
2.3996-2.550.17821450.1572751X-RAY DIFFRACTION100
2.55-2.74680.22141450.17022754X-RAY DIFFRACTION100
2.7468-3.02310.21061460.16552774X-RAY DIFFRACTION100
3.0231-3.46040.18441470.16252799X-RAY DIFFRACTION100
3.4604-4.35890.16661480.14332816X-RAY DIFFRACTION100
4.3589-40.12630.1841560.16482949X-RAY DIFFRACTION100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°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)
10.397-0.0016-0.22650.3808-0.35380.45940.0627-0.0636-0.0539-0.13510.00320.142-0.0029-0.45610.12430.20530.0203-0.07270.3113-0.00770.2882-35.439710.9116-9.1977
21.1862-0.0799-0.27610.1267-0.32321.0218-0.0277-0.16160.17440.13370.1236-0.0384-0.2855-0.1749-0.01140.06540.02450.02180.2167-0.0120.2011-30.026919.7686-0.0012
30.4919-0.37320.05470.70850.30060.7386-0.032-0.06370.06730.0020.03370.09090.0192-0.2212-0.04820.0817-0.0088-0.00650.1764-0.01860.1556-29.39678.9297-2.1578
40.7538-0.07930.30941.261-0.41281.560.03040.0059-0.138-0.071-0.04840.02290.4653-0.00640.01750.205-0.02420.01590.1164-0.01880.1176-24.4364-8.2199-2.4533
50.4013-0.4851-0.0950.65540.07530.3112-0.0808-0.180.17240.17340.0804-0.1353-0.31720.0725-0.00530.2630.0227-0.02870.2769-0.0210.2664-26.531720.26111.4408
60.00590.00450.01040.02820.00210.0192-0.03130.044-0.04870.0369-0.1820.01630.07590.1263-00.21880.01070.03010.241-0.00850.1461-12.9417-8.316116.0668
70.21210.10620.05140.19310.05470.4399-0.10770.21510.1961-0.3077-0.0351-0.181-0.3320.4488-0.010.2761-0.0031-0.01140.24350.0110.1792-13.65863.37184.1273
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN 'A' AND (RESID 14 THROUGH 54 )
2X-RAY DIFFRACTION2CHAIN 'A' AND (RESID 55 THROUGH 81 )
3X-RAY DIFFRACTION3CHAIN 'A' AND (RESID 82 THROUGH 139 )
4X-RAY DIFFRACTION4CHAIN 'A' AND (RESID 140 THROUGH 316 )
5X-RAY DIFFRACTION5CHAIN 'A' AND (RESID 317 THROUGH 350 )
6X-RAY DIFFRACTION6CHAIN 'B' AND (RESID 5 THROUGH 11 )
7X-RAY DIFFRACTION7CHAIN 'B' AND (RESID 12 THROUGH 24 )

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