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- PDB-4qfs: Structure of AMPK in complex with Br2-A769662core activator and S... -

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Basic information

Entry
Database: PDB / ID: 4qfs
TitleStructure of AMPK in complex with Br2-A769662core activator and STAUROSPORINE inhibitor
Components
  • (5'-AMP-activated protein kinase subunit ...) x 2
  • 5'-AMP-activated protein kinase catalytic subunit alpha-1
Keywordssignaling protein/inhibitor/activator / CBM / Kinase / AMPK / signaling protein-inhibitor-activator complex
Function / homology
Function and homology information


eukaryotic elongation factor-2 kinase activator activity / Energy dependent regulation of mTOR by LKB1-AMPK / Regulation of TP53 Activity through Phosphorylation / Macroautophagy / TP53 Regulates Metabolic Genes / nail development / positive regulation of mitochondrial transcription / [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase / [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase activity / regulation of stress granule assembly ...eukaryotic elongation factor-2 kinase activator activity / Energy dependent regulation of mTOR by LKB1-AMPK / Regulation of TP53 Activity through Phosphorylation / Macroautophagy / TP53 Regulates Metabolic Genes / nail development / positive regulation of mitochondrial transcription / [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase / [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase activity / regulation of stress granule assembly / negative regulation of tubulin deacetylation / histone H2BS36 kinase activity / cold acclimation / AMP-activated protein kinase activity / lipid droplet disassembly / phosphatidylethanolamine biosynthetic process / regulation of carbon utilization / positive regulation of skeletal muscle tissue development / CAMKK-AMPK signaling cascade / import into nucleus / phosphatidylcholine biosynthetic process / regulation of vesicle-mediated transport / protein localization to lysosome / negative regulation of hepatocyte apoptotic process / positive regulation of fatty acid oxidation / negative regulation of T cell mediated immune response to tumor cell / positive regulation of T cell mediated immune response to tumor cell / tau-protein kinase / nucleotide-activated protein kinase complex / protein kinase regulator activity / regulation of vascular permeability / negative regulation of TOR signaling / protein K6-linked ubiquitination / response to caffeine / regulation of glycolytic process / negative regulation of protein localization to nucleus / : / protein localization to lipid droplet / tau-protein kinase activity / lysosome organization / cholesterol biosynthetic process / lipid biosynthetic process / negative regulation of T cell activation / cellular response to stress / AMP binding / hepatocyte apoptotic process / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / fatty acid oxidation / positive regulation of release of cytochrome c from mitochondria / motor behavior / TORC1 signaling / positive regulation of translational initiation / cellular response to ethanol / fatty acid homeostasis / negative regulation of lipid catabolic process / response to UV / autophagosome assembly / cellular response to glucose starvation / positive regulation of protein localization / energy homeostasis / negative regulation of TORC1 signaling / negative regulation of insulin receptor signaling pathway / positive regulation of adipose tissue development / positive regulation of TORC1 signaling / negative regulation of translational initiation / positive regulation of autophagy / positive regulation of gluconeogenesis / cellular response to nutrient levels / cellular response to calcium ion / positive regulation of glycolytic process / cellular response to amino acid starvation / cellular response to starvation / regulation of microtubule cytoskeleton organization / response to activity / positive regulation of D-glucose import across plasma membrane / response to gamma radiation / protein localization to plasma membrane / circadian regulation of gene expression / response to hydrogen peroxide / cellular response to glucose stimulus / neuron cellular homeostasis / ADP binding / regulation of circadian rhythm / response to estrogen / protein destabilization / cellular response to xenobiotic stimulus / autophagy / glucose metabolic process / Wnt signaling pathway / positive regulation of T cell activation / cellular response to hydrogen peroxide / fatty acid biosynthetic process / cellular response to prostaglandin E stimulus / glucose homeostasis / positive regulation of cold-induced thermogenesis / cellular response to oxidative stress / protein-containing complex assembly / cellular response to hypoxia / protein phosphorylation / proteasome-mediated ubiquitin-dependent protein catabolic process
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 / : ...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 / Domain in cystathionine beta-synthase and other proteins. / CBS domain superfamily / CBS domain / CBS domain / CBS domain profile. / Special / Immunoglobulin E-set / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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. / Immunoglobulin-like fold / Immunoglobulins / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / Immunoglobulin-like / Sandwich / 2-Layer Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-32H / 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 / molecular replacement / Resolution: 3.55 Å
AuthorsCalabrese, M.F. / Kurumbail, R.G.
CitationJournal: Structure / Year: 2014
Title: Structural Basis for AMPK Activation: Natural and Synthetic Ligands Regulate Kinase Activity from Opposite Poles by Different Molecular Mechanisms.
Authors: Calabrese, M.F. / Rajamohan, F. / Harris, M.S. / Caspers, N.L. / Magyar, R. / Withka, J.M. / Wang, H. / Borzilleri, K.A. / Sahasrabudhe, P.V. / Hoth, L.R. / Geoghegan, K.F. / Han, S. / ...Authors: Calabrese, M.F. / Rajamohan, F. / Harris, M.S. / Caspers, N.L. / Magyar, R. / Withka, J.M. / Wang, H. / Borzilleri, K.A. / Sahasrabudhe, P.V. / Hoth, L.R. / Geoghegan, K.F. / Han, S. / Brown, J. / Subashi, T.A. / Reyes, A.R. / Frisbie, R.K. / Ward, J. / Miller, R.A. / Landro, J.A. / Londregan, A.T. / Carpino, P.A. / Cabral, S. / Smith, A.C. / Conn, E.L. / Cameron, K.O. / Qiu, X. / Kurumbail, R.G.
History
DepositionMay 21, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 6, 2014Provider: repository / Type: Initial release
Revision 1.1Aug 13, 2014Group: Database references
Revision 1.2Aug 20, 2014Group: Database references
Revision 1.3Aug 16, 2017Group: Refinement description / Source and taxonomy / Category: entity_src_gen / software
Revision 1.4Nov 22, 2017Group: Refinement description / Category: software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.date / _software.language / _software.location / _software.name / _software.type / _software.version
Revision 1.5Oct 9, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_entry_details.has_protein_modification / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)119,86813
Polymers118,2593
Non-polymers1,60910
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10910 Å2
ΔGint-141 kcal/mol
Surface area35560 Å2
MethodPISA
2
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

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)239,73526
Polymers236,5176
Non-polymers3,21820
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation10_444-y-1,-x-1,-z-1/61
Buried area25170 Å2
ΔGint-302 kcal/mol
Surface area67760 Å2
MethodPISA
Unit cell
Length a, b, c (Å)123.880, 123.880, 401.640
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122

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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 / Fragment: AMPK alpha 1 / Mutation: Deletion 470-524; replaced by ASGGPGGS
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Ampk1, Prkaa1 / Production host: Escherichia coli (E. coli)
References: UniProt: P54645, non-specific serine/threonine protein kinase, EC: 2.7.11.27, [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 / AMPK subunit beta-1 / AMPKb / 5'-AMP-activated protein kinase 40 kDa subunit


Mass: 23045.273 Da / Num. of mol.: 1 / Fragment: AMPK beta 1 / 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 / AMPK gamma1 / AMPK subunit gamma-1 / AMPKg


Mass: 37434.094 Da / Num. of mol.: 1 / Fragment: AMPK gamma 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 , 5 types, 10 molecules

#4: Chemical ChemComp-STU / STAUROSPORINE


Mass: 466.531 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H26N4O3 / Comment: anticancer, antifungal, antibiotic, alkaloid*YM
#5: Chemical ChemComp-32H / 2-bromo-3-(4-bromophenyl)-4-hydroxy-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile / Br2-A769662core


Mass: 426.083 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H6Br2N2O2S
#6: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Cl
#7: Chemical ChemComp-AMP / ADENOSINE MONOPHOSPHATE


Mass: 347.221 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H14N5O7P / Comment: AMP*YM
#8: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4

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Details

Has protein modificationY
Sequence detailsENGINEERED INSERTION ASGGPGGS

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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: 3.76 Å3/Da / Density % sol: 67.3 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop
Details: 750 mM Ammonium Sulfate, 500 mM Lithium Sulfate, 100 mM tri-Sodium Citrate, 1% Ethylene glycol, VAPOR DIFFUSION, HANGING DROP, temperature 295K

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.97 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: May 17, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 3.55→30 Å / Num. obs: 20989 / Redundancy: 6.7 % / Biso Wilson estimate: 44.67 Å2 / Rmerge(I) obs: 0.148

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
BUSTER-TNTBUSTER 2.11.5refinement
PDB_EXTRACT3.14data extraction
HKL-2000data reduction
BUSTER2.11.5refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.55→29.59 Å / Cor.coef. Fo:Fc: 0.8942 / Cor.coef. Fo:Fc free: 0.8483 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2692 1047 5.03 %RANDOM
Rwork0.2255 ---
obs0.2276 20802 90.54 %-
Displacement parametersBiso mean: 101.67 Å2
Baniso -1Baniso -2Baniso -3
1--6.6908 Å20 Å20 Å2
2---6.6908 Å20 Å2
3---13.3815 Å2
Refine analyzeLuzzati coordinate error obs: 0.828 Å
Refinement stepCycle: LAST / Resolution: 3.55→29.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6008 0 94 0 6102
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.016265HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.278583HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2020SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes122HARMONIC2
X-RAY DIFFRACTIONt_gen_planes947HARMONIC5
X-RAY DIFFRACTIONt_it6265HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion
X-RAY DIFFRACTIONt_other_torsion
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion851SEMIHARMONIC5
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_contact7429SEMIHARMONIC4
LS refinement shellResolution: 3.55→3.74 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.2762 142 4.73 %
Rwork0.2175 2861 -
all0.2202 3003 -
obs--90.54 %
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)
10.2989-0.1707-0.17581.58690.69552.60950.0940.04510.0482-0.1051-0.08780.1831-0.6876-0.29-0.00630.13450.0644-0.0058-0.1273-0.1024-0.273528.7835-75.4714-16.0284
21.6386-0.5964-1.5712-0.18910.86572.9340.01980.05040.2396-0.12760.06850.2578-0.5928-0.2492-0.08820.31530.00570.0537-0.0178-0.1102-0.06735.0754-67.5099-30.9143
33.505-3.1369-0.08824.23814.54193.6816-0.1196-0.75640.6686-0.35741.4672-0.8916-0.22820.7063-1.3476-0.02890.14070.19130.3431-0.52570.212721.7018-40.722716.5192
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A9 - 548
2X-RAY DIFFRACTION2{ B|* }B79 - 270
3X-RAY DIFFRACTION3{ C|* }C28 - 322

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