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- PDB-5kq5: AMPK bound to allosteric activator -

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Basic information

Entry
Database: PDB / ID: 5kq5
TitleAMPK bound to allosteric activator
Components
  • (5'-AMP-activated protein kinase subunit ...) x 2
  • 5'-AMP-activated protein kinase catalytic subunit alpha-1
KeywordsTRANSFERASE / Kinase Allosteric Activator
Function / homology
Function and homology information


eukaryotic elongation factor-2 kinase activator activity / Energy dependent regulation of mTOR by LKB1-AMPK / positive regulation of mitochondrial transcription / Regulation of TP53 Activity through Phosphorylation / Macroautophagy / TP53 Regulates Metabolic Genes / nail development / [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase / [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase activity / : ...eukaryotic elongation factor-2 kinase activator activity / Energy dependent regulation of mTOR by LKB1-AMPK / positive regulation of mitochondrial transcription / Regulation of TP53 Activity through Phosphorylation / Macroautophagy / TP53 Regulates Metabolic Genes / nail development / [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase / [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase activity / : / regulation of stress granule assembly / histone H2BS36 kinase activity / regulation of peptidyl-serine phosphorylation / cold acclimation / positive regulation of peptidyl-lysine acetylation / lipid droplet disassembly / regulation of bile acid secretion / import into nucleus / positive regulation of fatty acid oxidation / positive regulation of skeletal muscle tissue development / CAMKK-AMPK signaling cascade / regulation of vesicle-mediated transport / cellular response to organonitrogen compound / protein kinase regulator activity / negative regulation of TOR signaling / negative regulation of hepatocyte apoptotic process / tau-protein kinase / bile acid and bile salt transport / nucleotide-activated protein kinase complex / cellular response to ethanol / protein localization to lipid droplet / bile acid signaling pathway / response to caffeine / motor behavior / positive regulation of protein targeting to mitochondrion / lipid biosynthetic process / negative regulation of tubulin deacetylation / AMP-activated protein kinase activity / positive regulation of protein localization / tau-protein kinase activity / cholesterol biosynthetic process / AMP binding / fatty acid oxidation / cellular response to nutrient levels / fatty acid homeostasis / cellular response to glucose starvation / negative regulation of lipid catabolic process / regulation of microtubule cytoskeleton organization / positive regulation of autophagy / energy homeostasis / response to UV / positive regulation of gluconeogenesis / negative regulation of insulin receptor signaling pathway / negative regulation of TORC1 signaling / positive regulation of adipose tissue development / cellular response to calcium ion / positive regulation of glycolytic process / response to activity / ADP binding / cellular response to glucose stimulus / response to gamma radiation / positive regulation of glucose import / response to hydrogen peroxide / regulation of circadian rhythm / cellular response to hydrogen peroxide / Wnt signaling pathway / autophagy / neuron cellular homeostasis / cellular response to prostaglandin E stimulus / response to estrogen / fatty acid biosynthetic process / glucose metabolic process / rhythmic process / cellular response to xenobiotic stimulus / glucose homeostasis / cellular response to oxidative stress / positive regulation of cold-induced thermogenesis / cellular response to hypoxia / negative regulation of translation / non-specific serine/threonine protein kinase / protein kinase activity / intracellular signal transduction / nuclear speck / response to xenobiotic stimulus / apical plasma membrane / axon / negative regulation of gene expression / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / dendrite / neuronal cell body / chromatin binding / positive regulation of cell population proliferation / chromatin / protein-containing complex binding / positive regulation of gene expression / negative regulation of apoptotic process / protein kinase binding / positive regulation of DNA-templated transcription
Similarity search - Function
Double Stranded RNA Binding Domain - #60 / Double Stranded RNA Binding Domain / PRKAA1, UBA-like autoinhibitory domain / 5'-AMP-activated protein kinase alpha 1 catalytic subunit, C-terminal / : / AMP-activated protein kinase, alpha subunit, autoinhibitory domain / Association with the SNF1 complex (ASC) domain / ASC domain superfamily / 5'-AMP-activated protein kinase beta subunit, interaction domain / 5'-AMP-activated protein kinase beta subunit, interation domain ...Double Stranded RNA Binding Domain - #60 / Double Stranded RNA Binding Domain / PRKAA1, UBA-like autoinhibitory domain / 5'-AMP-activated protein kinase alpha 1 catalytic subunit, C-terminal / : / AMP-activated protein kinase, alpha subunit, autoinhibitory domain / Association with the SNF1 complex (ASC) domain / ASC domain superfamily / 5'-AMP-activated protein kinase beta subunit, interaction domain / 5'-AMP-activated protein kinase beta subunit, interation domain / AMPK, C-terminal adenylate sensor domain / Adenylate sensor of SNF1-like protein kinase / AMP-activated protein kinase, glycogen-binding domain / Glycogen recognition site of AMP-activated protein kinase / KA1 domain/Ssp2, C-terminal / Other non-globular / CBS domain superfamily / Domain in cystathionine beta-synthase and other proteins. / CBS domain / CBS domain / CBS domain profile. / Special / Immunoglobulin E-set / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Immunoglobulins / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Chem-6VT / ADENOSINE-5'-DIPHOSPHATE / ADENOSINE MONOPHOSPHATE / STAUROSPORINE / 5'-AMP-activated protein kinase catalytic subunit alpha-1 / 5'-AMP-activated protein kinase subunit gamma-1 / 5'-AMP-activated protein kinase subunit beta-1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.41 Å
AuthorsCalabrese, M.F. / Kurumbail, R.G.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Discovery and Preclinical Characterization of 6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic Acid (PF-06409577), a Direct Activator of Adenosine Monophosphate-activated ...Title: Discovery and Preclinical Characterization of 6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic Acid (PF-06409577), a Direct Activator of Adenosine Monophosphate-activated Protein Kinase (AMPK), for the Potential Treatment of Diabetic Nephropathy.
Authors: Cameron, K.O. / Kung, D.W. / Kalgutkar, A.S. / Kurumbail, R.G. / Miller, R. / Salatto, C.T. / Ward, J. / Withka, J.M. / Bhattacharya, S.K. / Boehm, M. / Borzilleri, K.A. / Brown, J.A. / ...Authors: Cameron, K.O. / Kung, D.W. / Kalgutkar, A.S. / Kurumbail, R.G. / Miller, R. / Salatto, C.T. / Ward, J. / Withka, J.M. / Bhattacharya, S.K. / Boehm, M. / Borzilleri, K.A. / Brown, J.A. / Calabrese, M. / Caspers, N.L. / Cokorinos, E. / Conn, E.L. / Dowling, M.S. / Edmonds, D.J. / Eng, H. / Fernando, D.P. / Frisbie, R. / Hepworth, D. / Landro, J. / Mao, Y. / Rajamohan, F. / Reyes, A.R. / Rose, C.R. / Ryder, T. / Shavnya, A. / Smith, A.C. / Tu, M. / Wolford, A.C. / Xiao, J.
History
DepositionJul 5, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 17, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 21, 2016Group: Database references
Revision 1.2Nov 1, 2017Group: Author supporting evidence / Database references / Derived calculations
Category: citation / pdbx_struct_assembly_auth_evidence / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _pdbx_struct_oper_list.symmetry_operation
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

Downloads & links

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Assembly

Deposited unit
A: 5'-AMP-activated protein kinase catalytic subunit alpha-1
B: 5'-AMP-activated protein kinase subunit beta-1
C: 5'-AMP-activated protein kinase subunit gamma-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)120,42613
Polymers118,2593
Non-polymers2,16810
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area12220 Å2
ΔGint-127 kcal/mol
Surface area35280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)124.500, 124.500, 402.250
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122
DetailsHetero-trimer (ABC) as determined with copurification, gel-filtration, functional evidence.

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Components

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Protein , 1 types, 1 molecules A

#1: Protein 5'-AMP-activated protein kinase catalytic subunit alpha-1 / AMPK subunit alpha-1 / Acetyl-CoA carboxylase kinase / ACACA kinase / Hydroxymethylglutaryl-CoA ...AMPK subunit alpha-1 / Acetyl-CoA carboxylase kinase / ACACA kinase / Hydroxymethylglutaryl-CoA reductase kinase / HMGCR kinase / Tau-protein kinase PRKAA1


Mass: 57779.137 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Prkaa1, Ampk1 / Production host: Escherichia coli (E. coli)
References: UniProt: P54645, non-specific serine/threonine protein kinase, [acetyl-CoA carboxylase] kinase, [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase, tau-protein kinase

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5'-AMP-activated protein kinase subunit ... , 2 types, 2 molecules BC

#2: Protein 5'-AMP-activated protein kinase subunit beta-1 / AMPKb / 5'-AMP-activated protein kinase 40 kDa subunit


Mass: 23045.273 Da / Num. of mol.: 1 / Fragment: residues 68-270 / Mutation: S108D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Prkab1 / Production host: Escherichia coli (E. coli) / References: UniProt: P80386
#3: Protein 5'-AMP-activated protein kinase subunit gamma-1 / AMPKg


Mass: 37434.094 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Prkag1 / Production host: Escherichia coli (E. coli) / References: UniProt: P80385

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Non-polymers , 6 types, 10 molecules

#4: Chemical ChemComp-STU / STAUROSPORINE / Staurosporine


Mass: 466.531 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H26N4O3 / Comment: anticancer, antifungal, antibiotic, alkaloid*YM
#5: Chemical ChemComp-6VT / 6-chloranyl-5-[4-(1-oxidanylcyclobutyl)phenyl]-1~{H}-indole-3-carboxylic acid


Mass: 341.788 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H16ClNO3
#6: Chemical
ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Cl
#7: Chemical ChemComp-AMP / ADENOSINE MONOPHOSPHATE / Adenosine monophosphate


Mass: 347.221 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H14N5O7P / Comment: AMP*YM
#8: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE / Adenosine diphosphate


Mass: 427.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
#9: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4

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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: 3.81 Å3/Da / Density % sol: 67.7 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop
Details: ~750 mM Ammonium Acetate, 500 mM Lithium Sulfate, 100 mM trisodium citrate, 1% ethylene glycol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Mar 26, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.4→30 Å / Num. obs: 25248 / % possible obs: 96.2 % / Redundancy: 4.2 % / Biso Wilson estimate: 89.73 Å2 / Rmerge(I) obs: 0.138 / Χ2: 1.375 / Net I/av σ(I): 12.371 / Net I/σ(I): 7.3 / Num. measured all: 105416
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
3.4-3.463.10.681194.2
3.46-3.523.40.577194.8
3.52-3.593.70.573196.7
3.59-3.663.90.532197.2
3.66-3.744.20.5197.6
3.74-3.834.30.367197.7
3.83-3.924.20.427197.3
3.92-4.034.40.29197.4
4.03-4.154.40.24197.3
4.15-4.284.50.2197.1
4.28-4.434.40.168197.1
4.43-4.614.40.139196.8
4.61-4.824.40.126196.3
4.82-5.074.40.119196.4
5.07-5.394.40.12196.6
5.39-5.84.40.118196.2
5.8-6.384.40.109195.7
6.38-7.294.30.079194.8
7.29-9.154.20.044194.9
9.15-303.90.034192.5

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Processing

Software
NameVersionClassification
BUSTER-TNT2.11.6refinement
HKL-2000data collection
HKL-2000data scaling
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4QFG

4qfg


Resolution: 3.41→29.9 Å / Cor.coef. Fo:Fc: 0.9079 / Cor.coef. Fo:Fc free: 0.8672 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.44 / SU Rfree Cruickshank DPI: 0.443
RfactorNum. reflection% reflectionSelection details
Rfree0.259 1248 4.95 %RANDOM
Rwork0.2207 ---
obs0.2225 25221 96.47 %-
Displacement parametersBiso max: 216.2 Å2 / Biso mean: 115.34 Å2 / Biso min: 57.94 Å2
Baniso -1Baniso -2Baniso -3
1--6.0578 Å20 Å20 Å2
2---6.0578 Å20 Å2
3---12.1157 Å2
Refine analyzeLuzzati coordinate error obs: 0.47 Å
Refinement stepCycle: final / Resolution: 3.41→29.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6089 0 141 0 6230
Biso mean--130.88 --
Num. residues----804
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2042SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes110HARMONIC2
X-RAY DIFFRACTIONt_gen_planes995HARMONIC5
X-RAY DIFFRACTIONt_it6380HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion879SEMIHARMONIC5
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_contact7314SEMIHARMONIC0
X-RAY DIFFRACTIONt_bond_d6380HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg8744HARMONIC21.16
X-RAY DIFFRACTIONt_omega_torsion2.32
X-RAY DIFFRACTIONt_other_torsion22.12
LS refinement shellResolution: 3.41→3.55 Å / Total num. of bins used: 13
RfactorNum. reflection% reflection
Rfree0.3017 123 4.51 %
Rwork0.2429 2604 -
all0.2455 2727 -
obs--94.59 %
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)
10.3509-0.1142-0.22831.35020.89592.36980.1233-0.04360.1406-0.1577-0.15070.1966-0.6186-0.35130.02750.34540.0693-0.01880.1956-0.1391-0.205929.1056-75.1895-15.9195
21.9767-0.6795-2.02690.38521.38433.61850.0120.02030.2315-0.12540.09320.1936-0.57-0.2278-0.10510.41140.1153-0.0080.1284-0.1005-0.171635.2615-67.5603-30.9449
33.8935-2.4422-1.29264.59253.00595.10090.0309-0.72860.6907-0.18830.7945-0.9241-0.37030.9308-0.8254-0.0060.17250.1080.246-0.3907-0.044622.0795-40.707616.4466
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A10 - 548
2X-RAY DIFFRACTION2{ B|* }B78 - 270
3X-RAY DIFFRACTION3{ C|* }C28 - 322

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