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- PDB-5uzk: Crystal Structure of PKA bound to an pyrrolo pyridine inhibitor -

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Basic information

Entry
Database: PDB / ID: 5uzk
TitleCrystal Structure of PKA bound to an pyrrolo pyridine inhibitor
Components
  • cAMP-dependent protein kinase catalytic subunit alphaCAMP-dependent pathway
  • cAMP-dependent protein kinase inhibitor alphaCAMP-dependent pathway
KeywordsTransferase/Transferase Inhibitor / PHOSPHORYLATION / KINASE / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


PKA-mediated phosphorylation of CREB / PKA-mediated phosphorylation of key metabolic factors / ROBO receptors bind AKAP5 / HDL assembly / high-density lipoprotein particle assembly / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism / negative regulation of cAMP-dependent protein kinase activity / regulation of protein binding / Rap1 signalling / nucleotide-activated protein kinase complex ...PKA-mediated phosphorylation of CREB / PKA-mediated phosphorylation of key metabolic factors / ROBO receptors bind AKAP5 / HDL assembly / high-density lipoprotein particle assembly / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism / negative regulation of cAMP-dependent protein kinase activity / regulation of protein binding / Rap1 signalling / nucleotide-activated protein kinase complex / renal water homeostasis / regulation of protein processing / protein localization to lipid droplet / regulation of bicellular tight junction assembly / cellular response to parathyroid hormone stimulus / cAMP-dependent protein kinase inhibitor activity / cell communication by electrical coupling involved in cardiac conduction / cAMP-dependent protein kinase / cellular response to cold / Loss of phosphorylation of MECP2 at T308 / sperm capacitation / regulation of osteoblast differentiation / CREB1 phosphorylation through the activation of Adenylate Cyclase / PKA activation / cAMP-dependent protein kinase activity / negative regulation of glycolytic process through fructose-6-phosphate / ciliary base / cAMP-dependent protein kinase complex / AMP-activated protein kinase activity / negative regulation of protein import into nucleus / postsynaptic modulation of chemical synaptic transmission / molecular function inhibitor activity / cellular response to glucagon stimulus / Triglyceride catabolism / protein kinase A regulatory subunit binding / protein kinase A catalytic subunit binding / plasma membrane raft / PKA activation in glucagon signalling / : / Regulation of MECP2 expression and activity / mesoderm formation / regulation of cardiac conduction / RET signaling / DARPP-32 events / Interleukin-3, Interleukin-5 and GM-CSF signaling / sperm flagellum / regulation of macroautophagy / regulation of cardiac muscle contraction / 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 / protein kinase A signaling / positive regulation of gluconeogenesis / regulation of ryanodine-sensitive calcium-release channel activity / Ion homeostasis / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / negative regulation of TORC1 signaling / Recruitment of mitotic centrosome proteins and complexes / sperm midpiece / Recruitment of NuMA to mitotic centrosomes / cellular response to epinephrine stimulus / calcium channel complex / Anchoring of the basal body to the plasma membrane / regulation of cytosolic calcium ion concentration / regulation of G2/M transition of mitotic cell cycle / regulation of heart rate / protein export from nucleus / protein serine/threonine/tyrosine kinase activity / CD209 (DC-SIGN) signaling / AURKA Activation by TPX2 / FCGR3A-mediated IL10 synthesis / acrosomal vesicle / positive regulation of protein export from nucleus / Regulation of insulin secretion / neural tube closure / 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of insulin secretion / mRNA processing / Vasopressin regulates renal water homeostasis via Aquaporins / VEGFA-VEGFR2 Pathway / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cytokine-mediated signaling pathway / GPER1 signaling / Regulation of PLK1 Activity at G2/M Transition / cellular response to heat / manganese ion binding / Factors involved in megakaryocyte development and platelet production / peptidyl-serine phosphorylation / dendritic spine / molecular adaptor activity / regulation of cell cycle
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-504 / cAMP-dependent protein kinase catalytic subunit alpha / cAMP-dependent protein kinase inhibitor alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
Oryctolagus cuniculus (rabbit)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.3 Å
AuthorsJacobs, M.D. / Brown, K.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2018
Title: ROCK inhibitors 3: Design, synthesis and structure-activity relationships of 7-azaindole-based Rho kinase (ROCK) inhibitors.
Authors: Bandarage, U.K. / Cao, J. / Come, J.H. / Court, J.J. / Gao, H. / Jacobs, M.D. / Marhefka, C. / Nanthakumar, S. / Green, J.
History
DepositionFeb 26, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 7, 2018Provider: repository / Type: Initial release
Revision 1.1Jul 11, 2018Group: Data collection / Database references / Category: citation
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.year
Revision 1.2Aug 22, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_volume ..._citation.journal_abbrev / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3Oct 4, 2023Group: 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

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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
I: cAMP-dependent protein kinase inhibitor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,2573
Polymers42,7822
Non-polymers4761
Water4,954275
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1740 Å2
ΔGint-1 kcal/mol
Surface area15810 Å2
MethodPISA
Unit cell
Length a, b, c (Å)73.170, 78.180, 80.260
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 40808.570 Da / Num. of mol.: 1 / Fragment: kinase domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRKACA, PKACA / Production host: Escherichia coli (E. coli) / References: UniProt: P17612, cAMP-dependent protein kinase
#2: Protein/peptide cAMP-dependent protein kinase inhibitor alpha / CAMP-dependent pathway / PKI-alpha / cAMP-dependent protein kinase inhibitor / muscle/brain isoform


Mass: 1973.177 Da / Num. of mol.: 1 / Fragment: UNP residues 6-23 / Source method: obtained synthetically / Source: (synth.) Oryctolagus cuniculus (rabbit) / References: UniProt: P61926
#3: Chemical ChemComp-504 / 2-{3-[3-(piperidin-4-yl)propoxy]phenyl}-N-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,3-thiazol-2-yl]acetamide


Mass: 475.606 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H29N5O2S
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 275 / 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: 2.69 Å3/Da / Density % sol: 54.33 % / Mosaicity: 0.21 °
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 7 / Details: 2% MPD, VAPOR DIFFUSION, HANGING DROP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Apr 20, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.3→26.71 Å / Num. obs: 20724 / % possible obs: 99 % / Redundancy: 3.6 % / Biso Wilson estimate: 46.03 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.063 / Rpim(I) all: 0.039 / Rrim(I) all: 0.074 / Net I/σ(I): 13.9 / Num. measured all: 73980 / Scaling rejects: 0
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsCC1/2Rpim(I) allRrim(I) all% possible all
2.3-2.433.60.2850.9680.1720.33499
7.28-26.713.20.0420.9970.0270.0596.5

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Processing

Software
NameVersionClassification
Aimless0.5.27data scaling
BUSTER2.11.7refinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: pdbid 2ERZ

2erz


Resolution: 2.3→26.71 Å / Cor.coef. Fo:Fc: 0.932 / Cor.coef. Fo:Fc free: 0.892 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.278 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.313 / SU Rfree Blow DPI: 0.237 / SU Rfree Cruickshank DPI: 0.23
RfactorNum. reflection% reflectionSelection details
Rfree0.253 1005 4.87 %RANDOM
Rwork0.188 ---
obs0.191 20619 98 %-
Displacement parametersBiso max: 125.41 Å2 / Biso mean: 38.9 Å2 / Biso min: 10.61 Å2
Baniso -1Baniso -2Baniso -3
1-3.7523 Å20 Å20 Å2
2---9.126 Å20 Å2
3---5.3738 Å2
Refine analyzeLuzzati coordinate error obs: 0.27 Å
Refinement stepCycle: final / Resolution: 2.3→26.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2886 0 35 275 3196
Biso mean--43.64 45.02 -
Num. residues----355
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1028SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes72HARMONIC2
X-RAY DIFFRACTIONt_gen_planes432HARMONIC5
X-RAY DIFFRACTIONt_it2999HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion373SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3668SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2999HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg4057HARMONIC21.07
X-RAY DIFFRACTIONt_omega_torsion2.92
X-RAY DIFFRACTIONt_other_torsion18.11
LS refinement shellResolution: 2.3→2.42 Å / Rfactor Rfree error: 0 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.338 164 5.82 %
Rwork0.225 2652 -
all0.231 2816 -
obs--93.34 %
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)
11.09880.31110.07090.95340.61532.0812-0.00160.0345-0.05110.00030.0369-0.07670.03920.255-0.0353-0.16960.0240.002-0.01440.0292-0.174327.6052.44412.5846
20.13790.2545-0.54770.5549-1.81.2216-0.01640.06990.07120.04970.0228-0.03820.0014-0.0851-0.0064-0.03160.0455-0.02370.08350.013-0.10614.2205-1.9895-10.9155
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A14 - 350
2X-RAY DIFFRACTION2{ I|* }I5 - 22

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