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- PDB-2gu8: Discovery of 2-Pyrimidyl-5-Amidothiophenes as Novel and Potent In... -

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Basic information

Entry
Database: PDB / ID: 2gu8
TitleDiscovery of 2-Pyrimidyl-5-Amidothiophenes as Novel and Potent Inhibitors for AKT: Synthesis and SAR Studies
Components
  • CAMP-dependent protein kinase, alpha-catalytic subunit
  • inhibitor of CAMP-dependent protein kinase
KeywordsSIGNALING PROTEIN / TRANSFERASE/INHIBITOR / CAMP-dependent protein kinase / PKA / Akt / Kinase / Drug Design / ternary complex / 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 / mitochondrial protein catabolic process / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism / regulation of protein binding / nucleotide-activated protein kinase complex / high-density lipoprotein particle assembly / Rap1 signalling ...PKA-mediated phosphorylation of CREB / PKA-mediated phosphorylation of key metabolic factors / ROBO receptors bind AKAP5 / HDL assembly / mitochondrial protein catabolic process / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism / regulation of protein binding / nucleotide-activated protein kinase complex / high-density lipoprotein particle assembly / Rap1 signalling / renal water homeostasis / regulation of protein processing / protein localization to lipid droplet / regulation of bicellular tight junction assembly / cellular response to parathyroid hormone stimulus / cell communication by electrical coupling involved in cardiac conduction / cAMP-dependent protein kinase / cellular response to cold / Loss of phosphorylation of MECP2 at T308 / regulation of osteoblast differentiation / CREB1 phosphorylation through the activation of Adenylate Cyclase / PKA activation / sperm capacitation / cAMP-dependent protein kinase activity / ciliary base / negative regulation of glycolytic process through fructose-6-phosphate / cAMP-dependent protein kinase complex / AMP-activated protein kinase activity / postsynaptic modulation of chemical synaptic transmission / cellular response to glucagon stimulus / Triglyceride catabolism / protein kinase A regulatory subunit binding / plasma membrane raft / PKA activation in glucagon signalling / : / Regulation of MECP2 expression and activity / mesoderm formation / RET signaling / DARPP-32 events / Interleukin-3, Interleukin-5 and GM-CSF signaling / regulation of cardiac muscle contraction / regulation of cardiac conduction / sperm flagellum / regulation of macroautophagy / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / Hedgehog 'off' state / negative regulation of smoothened signaling pathway / regulation of proteasomal protein catabolic process / Ion homeostasis / regulation of ryanodine-sensitive calcium-release channel activity / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / positive regulation of gluconeogenesis / Recruitment of mitotic centrosome proteins and complexes / sperm midpiece / negative regulation of TORC1 signaling / Recruitment of NuMA to mitotic centrosomes / protein kinase A signaling / Mitochondrial protein degradation / calcium channel complex / Anchoring of the basal body to the plasma membrane / cellular response to epinephrine stimulus / regulation of cytosolic calcium ion concentration / protein serine/threonine/tyrosine kinase activity / protein export from nucleus / regulation of heart rate / CD209 (DC-SIGN) signaling / AURKA Activation by TPX2 / FCGR3A-mediated IL10 synthesis / positive regulation of protein export from nucleus / acrosomal vesicle / 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of insulin secretion / mRNA processing / cytokine-mediated signaling pathway / VEGFA-VEGFR2 Pathway / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / GPER1 signaling / Regulation of PLK1 Activity at G2/M Transition / Factors involved in megakaryocyte development and platelet production / cellular response to heat / manganese ion binding / peptidyl-serine phosphorylation / dendritic spine / regulation of cell cycle / protein kinase activity / nuclear speck / mitochondrial matrix / protein domain specific binding / protein phosphorylation
Similarity search - Function
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. ...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-796 / cAMP-dependent protein kinase catalytic subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsMurray, J.M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2006
Title: Discovery of 2-pyrimidyl-5-amidothiophenes as potent inhibitors for AKT: synthesis and SAR studies
Authors: Lin, X. / Murray, J.M. / Rico, A.C. / Wang, M.X. / Chu, D.T. / Zhou, Y. / Del Rosario, M. / Kaufman, S. / Ma, S. / Fang, E. / Crawford, K. / Jefferson, A.B.
History
DepositionApr 28, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 1, 2007Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: CAMP-dependent protein kinase, alpha-catalytic subunit
C: inhibitor of CAMP-dependent protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,0773
Polymers41,6402
Non-polymers4361
Water3,063170
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2880 Å2
ΔGint-15 kcal/mol
Surface area16200 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.720, 75.165, 79.844
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, alpha-catalytic subunit / E.C.2.7.1.37 / PKA C-alpha


Mass: 39413.996 Da / Num. of mol.: 1 / Fragment: catalytic subunit
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli) / References: UniProt: P17612, EC: 2.7.1.37
#2: Protein/peptide inhibitor of CAMP-dependent protein kinase


Mass: 2226.411 Da / Num. of mol.: 1 / Source method: obtained synthetically
#3: Chemical ChemComp-796 / N-[(1S)-2-AMINO-1-(2,4-DICHLOROBENZYL)ETHYL]-5-[2-(METHYLAMINO)PYRIMIDIN-4-YL]THIOPHENE-2-CARBOXAMIDE / NOVARTIS 273796


Mass: 436.358 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H19Cl2N5OS
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 170 / 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: 2.62 Å3/Da / Density % sol: 53.04 %

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1.11587 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Oct 21, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.11587 Å / Relative weight: 1
ReflectionResolution: 2.2→79.81 Å / Num. obs: 22827 / % possible obs: 98.7 % / Redundancy: 3.7 % / Biso Wilson estimate: 37.24 Å2 / Rmerge(I) obs: 0.053
Reflection shellResolution: 2.2→2.32 Å / Redundancy: 2.7 % / Rmerge(I) obs: 0.358 / Mean I/σ(I) obs: 3.1 / Num. unique all: 3013 / Rsym value: 0.358 / % possible all: 93.1

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Processing

SoftwareName: REFMAC / Version: 5.2 / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→36.37 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.907 / SU B: 11.189 / SU ML: 0.169 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.271 / ESU R Free: 0.225 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26118 1160 5.2 %RANDOM
Rwork0.20279 ---
all0.2032 22827 --
obs0.20591 21339 98.56 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 49.672 Å2
Baniso -1Baniso -2Baniso -3
1-0.02 Å20 Å20 Å2
2---0.02 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 2.2→36.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2925 0 28 170 3123
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.0223028
X-RAY DIFFRACTIONr_angle_refined_deg1.7481.9634089
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8285355
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.97223.826149
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.3815.028529
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.981518
X-RAY DIFFRACTIONr_chiral_restr0.1320.2428
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.022306
X-RAY DIFFRACTIONr_nbd_refined0.2280.21467
X-RAY DIFFRACTIONr_nbtor_refined0.3170.22036
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1710.2208
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1310.225
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2830.23
X-RAY DIFFRACTIONr_mcbond_it1.1641.51838
X-RAY DIFFRACTIONr_mcangle_it1.78822859
X-RAY DIFFRACTIONr_scbond_it2.91131393
X-RAY DIFFRACTIONr_scangle_it4.1744.51230
LS refinement shellResolution: 2.2→2.257 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.344 71 -
Rwork0.249 1393 -
obs--89.43 %

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