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- PDB-6bx6: AMP-Activated protein kinase (AMPK) inhibition by SBI-0206965: al... -

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Basic information

Entry
Database: PDB / ID: 6bx6
TitleAMP-Activated protein kinase (AMPK) inhibition by SBI-0206965: alpha 2 kinase domain bound to SBI-0206965
Components5'-AMP-activated protein kinase catalytic subunit alpha-2
KeywordsTransferase/Transferase Inhibitor / Transferase / Serine/Threonine-protein kinase / Inhibitor / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


[hydroxymethylglutaryl-CoA reductase (NADPH)] kinase / [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase activity / : / regulation of stress granule assembly / histone H2BS36 kinase activity / AMPK inhibits chREBP transcriptional activation activity / positive regulation of peptidyl-lysine acetylation / lipid droplet disassembly / Lipophagy / Energy dependent regulation of mTOR by LKB1-AMPK ...[hydroxymethylglutaryl-CoA reductase (NADPH)] kinase / [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase activity / : / regulation of stress granule assembly / histone H2BS36 kinase activity / AMPK inhibits chREBP transcriptional activation activity / positive regulation of peptidyl-lysine acetylation / lipid droplet disassembly / Lipophagy / Energy dependent regulation of mTOR by LKB1-AMPK / negative regulation of TOR signaling / Carnitine metabolism / negative regulation of hepatocyte apoptotic process / nucleotide-activated protein kinase complex / protein localization to lipid droplet / response to muscle activity / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / Nuclear events mediated by NFE2L2 / lipid biosynthetic process / negative regulation of tubulin deacetylation / Macroautophagy / AMP-activated protein kinase activity / positive regulation of protein localization / cholesterol biosynthetic process / cellular response to nutrient levels / positive regulation of macroautophagy / regulation of macroautophagy / cellular response to glucose starvation / fatty acid homeostasis / positive regulation of autophagy / Activation of AMPK downstream of NMDARs / regulation of microtubule cytoskeleton organization / energy homeostasis / negative regulation of TORC1 signaling / cellular response to calcium ion / protein serine/threonine/tyrosine kinase activity / positive regulation of glycolytic process / Translocation of SLC2A4 (GLUT4) to the plasma membrane / cellular response to glucose stimulus / TP53 Regulates Metabolic Genes / regulation of circadian rhythm / Wnt signaling pathway / autophagy / cytoplasmic stress granule / cellular response to prostaglandin E stimulus / fatty acid biosynthetic process / rhythmic process / cellular response to xenobiotic stimulus / glucose homeostasis / cellular response to oxidative stress / Regulation of TP53 Activity through Phosphorylation / non-specific serine/threonine protein kinase / protein kinase activity / intracellular signal transduction / nuclear speck / axon / protein phosphorylation / negative regulation of gene expression / protein serine kinase activity / protein serine/threonine kinase activity / neuronal cell body / dendrite / chromatin binding / negative regulation of apoptotic process / Golgi apparatus / signal transduction / nucleoplasm / ATP binding / metal ion binding / nucleus / cytosol
Similarity search - Function
PRKAA2, UBA-like autoinhibitory domain / 5'-AMP-activated protein kinase catalytic subunit alpha-2, C-terminal / : / AMP-activated protein kinase, alpha subunit, autoinhibitory domain / AMPK, C-terminal adenylate sensor domain / Adenylate sensor of SNF1-like protein kinase / KA1 domain/Ssp2, C-terminal / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site ...PRKAA2, UBA-like autoinhibitory domain / 5'-AMP-activated protein kinase catalytic subunit alpha-2, C-terminal / : / AMP-activated protein kinase, alpha subunit, autoinhibitory domain / AMPK, C-terminal adenylate sensor domain / Adenylate sensor of SNF1-like protein kinase / KA1 domain/Ssp2, C-terminal / 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
Chem-EDJ / 5'-AMP-activated protein kinase catalytic subunit alpha-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsDite, T.A. / Langendorf, C.G. / Scott, J.W. / Oakhill, J.S.
Funding support Australia, 2items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)APP1098459 Australia
Jack Brockhoff FoundationJBF-4206, 2016 Australia
CitationJournal: J. Biol. Chem. / Year: 2018
Title: AMP-activated protein kinase selectively inhibited by the type II inhibitor SBI-0206965.
Authors: Dite, T.A. / Langendorf, C.G. / Hoque, A. / Galic, S. / Rebello, R.J. / Ovens, A.J. / Lindqvist, L.M. / Ngoei, K.R.W. / Ling, N.X.Y. / Furic, L. / Kemp, B.E. / Scott, J.W. / Oakhill, J.S.
History
DepositionDec 17, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 9, 2018Provider: repository / Type: Initial release
Revision 1.1Jun 20, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Feb 20, 2019Group: Author supporting evidence / Data collection / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Jan 8, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Oct 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: 5'-AMP-activated protein kinase catalytic subunit alpha-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,0712
Polymers31,5821
Non-polymers4891
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)38.430, 54.783, 143.188
Angle α, β, γ (deg.)90.00, 96.25, 90.00
Int Tables number5
Space group name H-MI121

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Components

#1: Protein 5'-AMP-activated protein kinase catalytic subunit alpha-2 / AMPK subunit alpha-2 / Acetyl-CoA carboxylase kinase / ACACA kinase / Hydroxymethylglutaryl-CoA ...AMPK subunit alpha-2 / Acetyl-CoA carboxylase kinase / ACACA kinase / Hydroxymethylglutaryl-CoA reductase kinase / HMGCR kinase


Mass: 31581.766 Da / Num. of mol.: 1 / Mutation: T172D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRKAA2, AMPK, AMPK2 / Plasmid: pET21b / Production host: Escherichia coli (E. coli) / Strain (production host): BL-21 / Variant (production host): Rosetta2
References: UniProt: P54646, non-specific serine/threonine protein kinase, [acetyl-CoA carboxylase] kinase, [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase
#2: Chemical ChemComp-EDJ / 2-({5-bromo-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}oxy)-N-methylbenzene-1-carboximidic acid


Mass: 489.319 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H21BrN4O5

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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: 2.37 Å3/Da / Density % sol: 48.15 % / Description: Clusters of long thin rectangular plates.
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 9.5
Details: 9-14 % ethanol, 5 mM magnesium chloride, 3-7 mM manganese chloride, 10 mM TCEP and 0.1 M Tris, pH 9.5.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.954 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 6, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.954 Å / Relative weight: 1
ReflectionResolution: 2.9→35.93 Å / Num. obs: 6688 / % possible obs: 99.9 % / Redundancy: 7 % / Biso Wilson estimate: 112.64 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.068 / Rpim(I) all: 0.028 / Net I/σ(I): 12.7
Reflection shellResolution: 2.9→3.08 Å / Redundancy: 7.2 % / Rmerge(I) obs: 0.739 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 1072 / CC1/2: 0.909 / Rpim(I) all: 0.315 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.10.2refinement
XDSOSX_64data reduction
Aimless6.3.0data scaling
PHASER6.3.0phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3AQV

3aqv


Resolution: 2.9→35.93 Å / Cor.coef. Fo:Fc: 0.923 / Cor.coef. Fo:Fc free: 0.893 / Rfactor Rfree error: 0 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.417
RfactorNum. reflection% reflectionSelection details
Rfree0.28 315 4.71 %RANDOM
Rwork0.252 ---
obs0.253 6686 99.9 %-
Displacement parametersBiso mean: 111.75 Å2
Baniso -1Baniso -2Baniso -3
1-10.8367 Å20 Å216.5722 Å2
2---11.5279 Å20 Å2
3---0.6912 Å2
Refine analyzeLuzzati coordinate error obs: 0.51 Å
Refinement stepCycle: 1 / Resolution: 2.9→35.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1837 0 31 0 1868
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0081947HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.982655HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d615SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes34HARMONIC2
X-RAY DIFFRACTIONt_gen_planes293HARMONIC5
X-RAY DIFFRACTIONt_it1947HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion1.67
X-RAY DIFFRACTIONt_other_torsion22.42
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion254SEMIHARMONIC5
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_contact2105SEMIHARMONIC4
LS refinement shellResolution: 2.9→3.24 Å / Rfactor Rfree error: 0 / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.254 -5.18 %
Rwork0.28 1793 -
all0.279 1891 -
obs--99.89 %
Refinement TLS params.Method: refined / Origin x: 46.6477 Å / Origin y: -47.1226 Å / Origin z: 24.3772 Å
111213212223313233
T-0.4489 Å2-0.0269 Å20.0349 Å2--0.4464 Å20.0939 Å2---0.3258 Å2
L5.0307 °2-1.7728 °22.6943 °2-2.3868 °2-0.9153 °2--7.8416 °2
S-0.0416 Å °0.7419 Å °0.3203 Å °0.2238 Å °-0.0807 Å °-0.1582 Å °0.2032 Å °0.2392 Å °0.1222 Å °
Refinement TLS groupSelection details: { A|* }

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