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- PDB-7axw: Crystal structure of the cAMP-dependent protein kinase A cocrysta... -

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Basic information

Entry
Database: PDB / ID: 7axw
TitleCrystal structure of the cAMP-dependent protein kinase A cocrystallized with 1-aminoisoquinoline and PKI (5-24)
Components
  • cAMP-dependent protein kinase catalytic subunit alpha
  • cAMP-dependent protein kinase inhibitor alpha
KeywordsTRANSFERASE / phosphotransferase / signalling pathways / glycogen metabolism / serine/threonine kinase
Function / homology
Function and homology information


negative regulation of cAMP/PKA signal transduction / cAMP-dependent protein kinase inhibitor activity / cAMP-dependent protein kinase / regulation of protein processing / cAMP-dependent protein kinase activity / protein localization to lipid droplet / regulation of bicellular tight junction assembly / cAMP-dependent protein kinase complex / cellular response to parathyroid hormone stimulus / negative regulation of protein import into nucleus ...negative regulation of cAMP/PKA signal transduction / cAMP-dependent protein kinase inhibitor activity / cAMP-dependent protein kinase / regulation of protein processing / cAMP-dependent protein kinase activity / protein localization to lipid droplet / regulation of bicellular tight junction assembly / cAMP-dependent protein kinase complex / cellular response to parathyroid hormone stimulus / negative regulation of protein import into nucleus / regulation of osteoblast differentiation / cellular response to cold / sperm capacitation / negative regulation of glycolytic process through fructose-6-phosphate / ciliary base / protein kinase A regulatory subunit binding / protein kinase A catalytic subunit binding / intracellular potassium ion homeostasis / mesoderm formation / plasma membrane raft / axoneme / sperm flagellum / postsynaptic modulation of chemical synaptic transmission / regulation of G2/M transition of mitotic cell cycle / regulation of proteasomal protein catabolic process / negative regulation of TORC1 signaling / protein serine/threonine/tyrosine kinase activity / cellular response to glucagon stimulus / positive regulation of gluconeogenesis / acrosomal vesicle / protein export from nucleus / positive regulation of phagocytosis / positive regulation of protein export from nucleus / negative regulation of smoothened signaling pathway / neural tube closure / neuromuscular junction / cellular response to glucose stimulus / positive regulation of cholesterol biosynthetic process / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / positive regulation of insulin secretion / mRNA processing / adenylate cyclase-activating G protein-coupled receptor signaling pathway / manganese ion binding / cellular response to heat / regulation of cell cycle / postsynapse / nuclear speck / protein domain specific binding / protein serine kinase activity / protein serine/threonine kinase activity / ubiquitin protein ligase binding / centrosome / protein kinase binding / perinuclear region of cytoplasm / glutamatergic synapse / magnesium ion binding / negative regulation of transcription by RNA polymerase II / mitochondrion / ATP binding / nucleus / cytoplasm / cytosol
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 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. ...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 / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
ISOQUINOLIN-1-AMINE / cAMP-dependent protein kinase catalytic subunit alpha / cAMP-dependent protein kinase inhibitor alpha
Similarity search - Component
Biological speciesCricetulus griseus (Chinese hamster)
Mus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.69 Å
AuthorsOebbeke, M. / Wienen-Schmidt, B. / Heine, A. / Klebe, G.
CitationJournal: To Be Published
Title: Fragment based drug design - Small chemical changes of fragments effecting big changes in binding
Authors: Oebbeke, M. / Wienen-Schmidt, B. / Gerber, H.-D. / Heine, A. / Klebe, G.
History
DepositionNov 10, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 24, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)43,4843
Polymers43,3402
Non-polymers1441
Water5,314295
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1900 Å2
ΔGint0 kcal/mol
Surface area16810 Å2
MethodPISA
Unit cell
Length a, b, c (Å)73.113, 107.584, 58.076
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein cAMP-dependent protein kinase catalytic subunit alpha / PKA C-alpha


Mass: 41113.766 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Cricetulus griseus (Chinese hamster) / Gene: PRKACA / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P25321, 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.) Mus musculus (house mouse) / References: UniProt: P63248
#3: Chemical ChemComp-1SQ / ISOQUINOLIN-1-AMINE / 1-AMINO-ISOQUINOLINE


Mass: 144.173 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H8N2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 295 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.77 Å3/Da / Density % sol: 55.6 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.9
Details: 30mM MBT, 1mM DTT, 0.1mM EDTA, 75mM LiCl, 0.3mM Mega8, 0.07mM PKI, 10mM of 1-aminoisoquinoline (solved in DMSO, 100mM) and 20% (v/v) MeOH

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 18, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.69→45.48 Å / Num. obs: 48217 / % possible obs: 92.6 % / Redundancy: 5.1 % / Biso Wilson estimate: 20.09 Å2 / Rsym value: 0.051 / Net I/σ(I): 19.3
Reflection shellResolution: 1.69→1.79 Å / Mean I/σ(I) obs: 2.61 / Num. unique obs: 6544 / Rsym value: 0.448 / % possible all: 78.9

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Processing

Software
NameVersionClassification
Cootmodel building
PHENIX1.17.1_3660refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1Q8W

1q8w


Resolution: 1.69→45.48 Å / SU ML: 0.1771 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 22.1649
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2193 2411 5 %
Rwork0.1812 45798 -
obs0.1832 48209 92.64 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 28.32 Å2
Refinement stepCycle: LAST / Resolution: 1.69→45.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2877 0 11 295 3183
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00923030
X-RAY DIFFRACTIONf_angle_d0.98144123
X-RAY DIFFRACTIONf_chiral_restr0.0538447
X-RAY DIFFRACTIONf_plane_restr0.0068540
X-RAY DIFFRACTIONf_dihedral_angle_d16.96511079
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.69-1.720.25621090.23752073X-RAY DIFFRACTION71.87
1.72-1.760.28861240.22272355X-RAY DIFFRACTION81.76
1.76-1.80.25311270.21672412X-RAY DIFFRACTION84.75
1.8-1.850.26421280.21022438X-RAY DIFFRACTION85.25
1.85-1.90.25581290.21092447X-RAY DIFFRACTION85.3
1.9-1.950.26231340.2062552X-RAY DIFFRACTION88.09
1.95-2.020.2231340.19022547X-RAY DIFFRACTION89.07
2.02-2.090.1991420.19662698X-RAY DIFFRACTION93.39
2.09-2.170.26031480.19372806X-RAY DIFFRACTION97.69
2.17-2.270.2331510.18942877X-RAY DIFFRACTION99.31
2.27-2.390.22321520.1872889X-RAY DIFFRACTION99.38
2.39-2.540.221520.18182890X-RAY DIFFRACTION99.61
2.54-2.740.21391530.18962895X-RAY DIFFRACTION99.8
2.74-3.010.23251540.18562935X-RAY DIFFRACTION99.94
3.01-3.450.24071550.17772932X-RAY DIFFRACTION99.68
3.45-4.340.17941550.14732962X-RAY DIFFRACTION99.43
4.35-45.480.19591640.17213090X-RAY DIFFRACTION99.27
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)
12.125044665311.1081888424-2.032582349884.28499563372-3.037775724266.53429901312-0.176729666795-0.0132396644029-0.164176819801-0.169518151252-0.0585919358847-0.294645670710.5423532419920.2360122946270.2742146292820.165495074380.03285882722780.02521552440440.231686080437-0.02825107424150.140915952129-8.918723744321.24679726452-9.30992351263
26.4193128614-1.138326930710.04320876601963.1956953271-1.866424378061.817143605090.1764528556970.2260616201660.274394850274-0.0862998062832-0.1172786823530.235242231913-0.1444586149270.0895240252031-0.1196525744570.2577563957030.02048791805850.02427676030970.320199474763-0.02881209556540.166371725292-24.063117645329.7348943176-25.8573746505
34.707977374621.291318909552.574934531554.12691420752-0.09406112391942.64697388861-0.132178116788-0.2445412117060.6369214014190.0915399857869-0.1921998085550.0338732353973-0.386348285203-0.08996756197260.2908650320670.234261917994-0.02710789286610.0231944295360.2253452569390.008322395084850.190184195565-13.460066078931.4886703146-17.0010799801
41.166248996710.1615661953460.01000542811510.824194195763-0.1171311002381.06022511097-0.03685029749880.1250265496420.0260793994473-0.0724606219016-0.005107330207340.018633986774-0.0821919631626-0.1018221005680.02500870846390.1293851251640.00850005017308-0.01417917425290.121560759216-0.006216459770440.110024278408-22.35081403618.9042744398-10.6161391017
56.86453509394.77698841515.6085448624.43478743684.040717519875.751154595170.006525033898710.1441622904240.0620646120963-0.112378691813-0.00266738563313-0.256931531241-0.1394756427630.2319497575870.05349883885620.164820008486-0.02799570401290.007090198072980.1348584577190.004867715086780.207472215594-9.6580688658423.3943821273-5.70123383516
63.335908883180.8855160959620.03304352209872.241978840570.1459971915821.51355575098-0.0211160881001-0.3349870149770.2501695555890.09074280785270.00848433300338-0.0861840092403-0.1626093201090.0661657740718-0.006480682419350.1065716610550.00263253257032-0.01700513921730.121656936073-0.01286215055750.108729337007-17.566581635323.09025846137.06393919515
73.31060188368-0.229012552263-1.075364394622.992384077470.6004996304642.58715460815-0.0199606588856-0.213827606076-0.01267783938090.181916577080.0979379865932-0.2294432181940.06861923663430.175420998845-0.07717304258580.1415443159770.020169462195-0.02670653950050.1380262804490.03368038628140.122801162163-17.42253656319.157978106378.66874864937
86.497404561091.65381635055-0.264927622310.7166116518020.2012767916918.626245016250.02387097937330.20253147550.207908612139-0.236808139962-0.0102260889010.02444699368910.440757270176-0.141702500394-0.03864989255340.1325906105-0.05684114777-0.01313820832760.096555648149-0.03789112031710.157336322882-26.04146242464.30631739435-9.79747383532
97.071580663442.31370404176-0.7534975861762.3088222556-1.994399894172.56249510224-0.03262800716640.1408997734770.8272473293010.0538781100698-0.003506312596290.320735908503-0.534368855252-0.04822761987940.02259870187970.3429867826290.0355345083787-0.009496728189930.234511678623-0.05324155473330.248078420857-22.172222040534.7662049227-20.6711968971
104.595992574245.695020811-1.829688967739.301028998351.021224642685.59822652896-0.107793332542-0.4321042478350.1407919828870.302945587513-0.08354731292730.2752710311770.0199894347709-0.1646332316050.2574050633170.1958182889270.06443727182710.008954956345730.2293537203380.01616373352210.14908973837-34.084228646926.173287230312.0857939297
116.25888885282-3.12269137815-3.473541658615.42308361130.9292339917312.15149599868-0.161274007544-0.2064315029560.5201047644150.02064221745020.0083627877684-0.139519275536-0.3465504759510.06781486841180.156798923710.1620171088210.0311936971268-0.0396005099040.1899622505770.007626955556990.185030750395-25.301184652231.20550270282.07446495511
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid -2 through 31 )
2X-RAY DIFFRACTION2chain 'A' and (resid 32 through 67 )
3X-RAY DIFFRACTION3chain 'A' and (resid 68 through 97 )
4X-RAY DIFFRACTION4chain 'A' and (resid 98 through 179 )
5X-RAY DIFFRACTION5chain 'A' and (resid 180 through 198 )
6X-RAY DIFFRACTION6chain 'A' and (resid 199 through 252 )
7X-RAY DIFFRACTION7chain 'A' and (resid 253 through 297 )
8X-RAY DIFFRACTION8chain 'A' and (resid 298 through 316 )
9X-RAY DIFFRACTION9chain 'A' and (resid 317 through 350 )
10X-RAY DIFFRACTION10chain 'B' and (resid 5 through 12 )
11X-RAY DIFFRACTION11chain 'B' and (resid 13 through 22 )

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