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- PDB-6b1u: Structure of full-length human AMPK (a2b1g1) in complex with a sm... -

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Basic information

Entry
Database: PDB / ID: 6b1u
TitleStructure of full-length human AMPK (a2b1g1) in complex with a small molecule activator SC4
Components
  • (5'-AMP-activated protein kinase subunit ...) x 2
  • 5'-AMP-activated protein kinase catalytic subunit alpha-2
KeywordsTRANSFERASE / Phosphorylated / Active / Heterotrimer / Kinase.
Function / homology
Function and homology information


nail development / [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase / [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase activity / regulation of stress granule assembly / AMPK inhibits chREBP transcriptional activation activity / histone H2BS36 kinase activity / cAMP-dependent protein kinase regulator activity / AMP-activated protein kinase activity / lipid droplet disassembly / Lipophagy ...nail development / [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase / [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase activity / regulation of stress granule assembly / AMPK inhibits chREBP transcriptional activation activity / histone H2BS36 kinase activity / cAMP-dependent protein kinase regulator activity / AMP-activated protein kinase activity / lipid droplet disassembly / Lipophagy / regulation of carbon utilization / import into nucleus / nucleotide-activated protein kinase complex / negative regulation of hepatocyte apoptotic process / Energy dependent regulation of mTOR by LKB1-AMPK / Carnitine shuttle / protein kinase regulator activity / negative regulation of TOR signaling / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / Nuclear events mediated by NFE2L2 / regulation of glycolytic process / cAMP-dependent protein kinase activity / protein localization to lipid droplet / negative regulation of tubulin deacetylation / AMP binding / Macroautophagy / cholesterol biosynthetic process / lipid biosynthetic process / response to muscle activity / positive regulation of protein kinase activity / positive regulation of macroautophagy / regulation of macroautophagy / fatty acid homeostasis / cellular response to nutrient levels / cellular response to glucose starvation / energy homeostasis / Activation of AMPK downstream of NMDARs / positive regulation of protein localization / negative regulation of TORC1 signaling / positive regulation of gluconeogenesis / protein serine/threonine/tyrosine kinase activity / positive regulation of autophagy / cellular response to calcium ion / regulation of microtubule cytoskeleton organization / positive regulation of glycolytic process / TP53 Regulates Metabolic Genes / Translocation of SLC2A4 (GLUT4) to the plasma membrane / cellular response to glucose stimulus / regulation of circadian rhythm / ADP binding / autophagy / cellular response to xenobiotic stimulus / Wnt signaling pathway / cytoplasmic stress granule / fatty acid biosynthetic process / rhythmic process / glucose homeostasis / cellular response to prostaglandin E stimulus / positive regulation of cold-induced thermogenesis / cellular response to oxidative stress / spermatogenesis / Regulation of TP53 Activity through Phosphorylation / protein phosphorylation / non-specific serine/threonine protein kinase / protein kinase activity / regulation of cell cycle / nuclear speck / ciliary basal body / axon / negative regulation of gene expression / protein serine kinase activity / neuronal cell body / protein serine/threonine kinase activity / dendrite / chromatin binding / protein kinase binding / negative regulation of apoptotic process / protein-containing complex binding / Golgi apparatus / signal transduction / nucleoplasm / ATP binding / metal ion binding / nucleus / membrane / cytoplasm / 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 / : / 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 ...PRKAA2, UBA-like autoinhibitory domain / 5'-AMP-activated protein kinase catalytic subunit alpha-2, 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 / Domain in cystathionine beta-synthase and other proteins. / CBS domain superfamily / CBS domain / CBS domain / CBS domain profile. / Immunoglobulin E-set / 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 / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
ADENOSINE MONOPHOSPHATE / Chem-CG7 / IMIDAZOLE / STAUROSPORINE / 5'-AMP-activated protein kinase subunit gamma-1 / 5'-AMP-activated protein kinase catalytic subunit alpha-2 / 5'-AMP-activated protein kinase subunit beta-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.77 Å
AuthorsNgoei, K.R.W. / Langendorf, C.G. / Ling, N.X.Y. / Hoque, A. / Johnson, S. / Camerino, M.C. / Walker, S.R. / Bozikis, Y.E. / Dite, T.A. / Ovens, A.J. ...Ngoei, K.R.W. / Langendorf, C.G. / Ling, N.X.Y. / Hoque, A. / Johnson, S. / Camerino, M.C. / Walker, S.R. / Bozikis, Y.E. / Dite, T.A. / Ovens, A.J. / Smiles, W.J. / Jacobs, R. / Huang, H. / Parker, M.W. / Scott, J.W. / Rider, M.H. / Kemp, B.E. / Foitzik, R.C. / Baell, J.B. / Oakhill, J.S.
Funding support Australia, 4items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)APP1098459 Australia
Australian Research Council (ARC)FT130100988 Australia
THe Marian and EH Flack TrustEH Flack Fellowship Australia
Jack Brockhoff FoundationJBF 4206, 2016 Australia
CitationJournal: Cell Chem Biol / Year: 2018
Title: Structural Determinants for Small-Molecule Activation of Skeletal Muscle AMPK alpha 2 beta 2 gamma 1 by the Glucose Importagog SC4.
Authors: Ngoei, K.R.W. / Langendorf, C.G. / Ling, N.X.Y. / Hoque, A. / Varghese, S. / Camerino, M.A. / Walker, S.R. / Bozikis, Y.E. / Dite, T.A. / Ovens, A.J. / Smiles, W.J. / Jacobs, R. / Huang, H. ...Authors: Ngoei, K.R.W. / Langendorf, C.G. / Ling, N.X.Y. / Hoque, A. / Varghese, S. / Camerino, M.A. / Walker, S.R. / Bozikis, Y.E. / Dite, T.A. / Ovens, A.J. / Smiles, W.J. / Jacobs, R. / Huang, H. / Parker, M.W. / Scott, J.W. / Rider, M.H. / Foitzik, R.C. / Kemp, B.E. / Baell, J.B. / Oakhill, J.S.
History
DepositionSep 19, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 25, 2018Provider: repository / Type: Initial release
Revision 1.1May 2, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_id_ISSN / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jul 4, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.name
Revision 1.3Jan 1, 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
Revision 1.5Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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-2
B: 5'-AMP-activated protein kinase subunit beta-1
C: 5'-AMP-activated protein kinase catalytic subunit alpha-2
D: 5'-AMP-activated protein kinase subunit beta-1
E: 5'-AMP-activated protein kinase subunit gamma-1
F: 5'-AMP-activated protein kinase subunit gamma-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)268,63115
Polymers265,2976
Non-polymers3,3359
Water3,081171
1
A: 5'-AMP-activated protein kinase catalytic subunit alpha-2
B: 5'-AMP-activated protein kinase subunit beta-1
E: 5'-AMP-activated protein kinase subunit gamma-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)134,2817
Polymers132,6483
Non-polymers1,6334
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area15930 Å2
ΔGint-99 kcal/mol
Surface area41410 Å2
MethodPISA
2
C: 5'-AMP-activated protein kinase catalytic subunit alpha-2
D: 5'-AMP-activated protein kinase subunit beta-1
F: 5'-AMP-activated protein kinase subunit gamma-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)134,3508
Polymers132,6483
Non-polymers1,7025
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area16340 Å2
ΔGint-99 kcal/mol
Surface area42430 Å2
MethodPISA
Unit cell
Length a, b, c (Å)75.827, 133.897, 141.725
Angle α, β, γ (deg.)90.00, 92.74, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 2 molecules AC

#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: 63918.051 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRKAA2, AMPK, AMPK2 / Plasmid: pETDuet-1 / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta (DE3)
References: UniProt: P54646, non-specific serine/threonine protein kinase, EC: 2.7.11.27, [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase

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5'-AMP-activated protein kinase subunit ... , 2 types, 4 molecules BDEF

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


Mass: 30504.299 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRKAB1, AMPK / Plasmid: pRSFDuet-1 / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta (DE3) / References: UniProt: Q9Y478
#3: Protein 5'-AMP-activated protein kinase subunit gamma-1 / AMPKg


Mass: 38225.914 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRKAG1 / Plasmid: pETDuet-1 / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta (DE3) / References: UniProt: P54619

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Non-polymers , 5 types, 180 molecules

#4: Chemical ChemComp-STU / STAUROSPORINE


Mass: 466.531 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H26N4O3 / Comment: antibiotic*YM
#5: Chemical ChemComp-CG7 / 5-{[6-chloro-5-(2'-hydroxy[1,1'-biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy}-2-methylbenzoic acid


Mass: 471.892 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H18ClN3O4 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-IMD / IMIDAZOLE


Mass: 69.085 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H5N2
#7: Chemical
ChemComp-AMP / ADENOSINE MONOPHOSPHATE


Mass: 347.221 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H14N5O7P / Comment: AMP*YM
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 171 / Source method: isolated from a natural source / Formula: H2O

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Details

Has protein modificationY

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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: 3.16 Å3/Da / Density % sol: 61.1 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.2
Details: 8% PEG 3350, 0.1 M MgCl2, 1.0% glucose, 0.001% cocamidopropyl betaine and 0.1 M imidazole.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.9537 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Dec 4, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 2.77→48.64 Å / Num. obs: 71788 / % possible obs: 99.8 % / Redundancy: 3.3 % / Biso Wilson estimate: 76.72 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.074 / Rpim(I) all: 0.048 / Net I/σ(I): 10.5
Reflection shellResolution: 2.77→2.83 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.632 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 4646 / CC1/2: 0.652 / Rpim(I) all: 0.412 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.10.2refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ZHX

4zhx


Resolution: 2.77→48.64 Å / Cor.coef. Fo:Fc: 0.932 / Cor.coef. Fo:Fc free: 0.911 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.606 / Cross valid method: FREE R-VALUE / σ(F): 0 / SU R Blow DPI: 0.531 / SU Rfree Blow DPI: 0.275 / SU Rfree Cruickshank DPI: 0.286
RfactorNum. reflection% reflectionSelection details
Rfree0.226 3627 5.05 %RANDOM
Rwork0.194 ---
obs0.196 71762 99.8 %-
Displacement parametersBiso mean: 66.36 Å2
Baniso -1Baniso -2Baniso -3
1-0.2717 Å20 Å2-5.7149 Å2
2---5.6706 Å20 Å2
3---5.3989 Å2
Refine analyzeLuzzati coordinate error obs: 0.36 Å
Refinement stepCycle: 1 / Resolution: 2.77→48.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14510 0 277 182 14969
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00815198HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0120731HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d5006SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes296HARMONIC2
X-RAY DIFFRACTIONt_gen_planes2198HARMONIC5
X-RAY DIFFRACTIONt_it15198HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.01
X-RAY DIFFRACTIONt_other_torsion17.69
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion2011SEMIHARMONIC5
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_contact16650SEMIHARMONIC4
LS refinement shellResolution: 2.77→2.84 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.272 266 5.02 %
Rwork0.242 5032 -
all0.244 5298 -
obs--99.96 %
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)
12.03231.1852-1.17341.2536-0.47620.9188-0.07420.11530.0113-0.10980.099-0.04990.1479-0.0853-0.0247-0.1737-0.0169-0.0667-0.0116-0.0158-0.06711.163853.6043-22.076
21.67071.7766-1.32282.0221-1.51021.5406-0.2780.067-0.1584-0.17810.202-0.22090.39950.06730.076-0.1470.07830.0427-0.25150.0332-0.21272.973436.0527-19.1068
31.4076-0.87830.82341.1306-0.55321.2023-0.2029-0.32010.03790.25890.26890.0889-0.2754-0.248-0.066-0.09040.12770.0351-0.11410.0029-0.1266-36.11545.5559-50.5487
40.8071-1.15980.61642.1942-1.5810.9592-0.1648-0.2110.07360.37410.2248-0.0418-0.26790.0441-0.06-0.06360.0873-0.1075-0.2007-0.0678-0.1942-34.86324.6059-52.6795
51.94720.8196-1.49111.8718-0.45212.36450.0865-0.16540.18310.07670.0083-0.1221-0.33870.2502-0.0949-0.20720.0362-0.0136-0.179-0.011-0.136335.869777.7248-33.4083
61.5864-0.46960.84531.0325-0.24723.1044-0.1048-0.2329-0.08960.04650.1302-0.18290.12160.3543-0.0254-0.19150.0807-0.0516-0.0943-0.0083-0.1697-2.2804-15.8287-35.7343
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }
3X-RAY DIFFRACTION3{ C|* }
4X-RAY DIFFRACTION4{ D|* }
5X-RAY DIFFRACTION5{ E|* }
6X-RAY DIFFRACTION6{ F|* }

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