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- PDB-6b2e: Structure of full length human AMPK (a2b2g1) in complex with a sm... -

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Basic information

Entry
Database: PDB / ID: 6b2e
TitleStructure of full length human AMPK (a2b2g1) 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


[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 / import into nucleus ...[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 / import into nucleus / cAMP-dependent protein kinase regulator activity / protein kinase regulator activity / Energy dependent regulation of mTOR by LKB1-AMPK / negative regulation of TOR signaling / negative regulation of hepatocyte apoptotic process / Carnitine metabolism / 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 / regulation of glycolytic process / cAMP-dependent protein kinase activity / negative regulation of tubulin deacetylation / Macroautophagy / AMP-activated protein kinase activity / positive regulation of protein localization / cholesterol biosynthetic process / AMP binding / cellular response to nutrient levels / positive regulation of macroautophagy / fatty acid homeostasis / regulation of macroautophagy / positive regulation of protein kinase activity / cellular response to glucose starvation / Activation of AMPK downstream of NMDARs / regulation of microtubule cytoskeleton organization / positive regulation of autophagy / 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 / ADP binding / 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 / positive regulation of cold-induced thermogenesis / spermatogenesis / Regulation of TP53 Activity through Phosphorylation / non-specific serine/threonine protein kinase / protein kinase activity / intracellular signal transduction / nuclear speck / 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 gene expression / negative regulation of apoptotic process / protein kinase binding / Golgi apparatus / signal transduction / nucleoplasm / ATP binding / membrane / metal ion binding / nucleus / cytosol / cytoplasm
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 / AMPK, C-terminal adenylate sensor domain / Adenylate sensor of SNF1-like protein kinase ...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 / CBS domain superfamily / Domain in cystathionine beta-synthase and other proteins. / CBS domain / CBS domain / CBS domain profile. / 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 / 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
Similarity search - Domain/homology
beta-cyclodextrin / ADENOSINE MONOPHOSPHATE / Chem-CG7 / STAUROSPORINE / 5'-AMP-activated protein kinase subunit beta-2 / 5'-AMP-activated protein kinase subunit gamma-1 / 5'-AMP-activated protein kinase catalytic subunit alpha-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.8 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 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Non-polymer description / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / entity_name_com / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_molecule_features / pdbx_nonpoly_scheme / struct_conn / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.type_symbol / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.id / _chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.pdbx_synonyms / _chem_comp.type / _entity.formula_weight / _entity.pdbx_description / _entity.src_method / _entity.type
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Oct 4, 2023Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _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-2
B: 5'-AMP-activated protein kinase subunit beta-2
C: 5'-AMP-activated protein kinase subunit gamma-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)135,3528
Polymers132,5663
Non-polymers2,7865
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area14990 Å2
ΔGint-114 kcal/mol
Surface area44300 Å2
MethodPISA
Unit cell
Length a, b, c (Å)113.936, 118.848, 138.096
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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

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


Mass: 30422.189 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRKAB2 / Plasmid: pRSFDuet-1 / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta (DE3) / References: UniProt: O43741
#3: Protein 5'-AMP-activated protein kinase subunit gamma-1 / AMPKg


Mass: 38225.914 Da / Num. of mol.: 1
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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Protein / Sugars , 2 types, 2 molecules A

#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.: 1
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, [acetyl-CoA carboxylase] kinase, [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase
#4: Polysaccharide Cycloheptakis-(1-4)-(alpha-D-glucopyranose) / beta-cyclodextrin / Cyclodextrin


Type: oligosaccharide, Oligosaccharide / Class: Drug delivery / Mass: 1153.001 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: cyclic oligosaccharide / References: beta-cyclodextrin
DescriptorTypeProgram
WURCS=2.0/1,7,7/[a2122h-1a_1-5]/1-1-1-1-1-1-1/a1-g4_a4-b1_b4-c1_c4-d1_d4-e1_e4-f1_f4-g1WURCSPDB2Glycan 1.1.0

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Non-polymers , 3 types, 4 molecules

#5: 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
#6: 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.: 1 / Source method: obtained synthetically / Formula: C26H18ClN3O4
#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

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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: 3.53 Å3/Da / Density % sol: 65.12 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 6-8% PEG 3350, 0.1 M MgCl2, 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: Jul 21, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 3.8→48.15 Å / Num. obs: 17814 / % possible obs: 94 % / Redundancy: 6.4 % / Biso Wilson estimate: 89.66 Å2 / CC1/2: 0.986 / Rmerge(I) obs: 0.202 / Rpim(I) all: 0.082 / Net I/σ(I): 8
Reflection shellResolution: 3.8→4.25 Å / Rmerge(I) obs: 0.868 / Mean I/σ(I) obs: 2.4 / Num. unique obs: 4750 / CC1/2: 0.659 / Rpim(I) all: 0.447 / % possible all: 89.6

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Processing

Software
NameVersionClassification
BUSTER2.10.2refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6BIU, 4RER

6biu
PDB Unreleased entry

4rer


Resolution: 3.8→48.15 Å / Cor.coef. Fo:Fc: 0.895 / Cor.coef. Fo:Fc free: 0.886 / Rfactor Rfree error: 0 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.658
RfactorNum. reflection% reflectionSelection details
Rfree0.277 920 5.18 %RANDOM
Rwork0.244 ---
obs0.246 17764 93.3 %-
Displacement parametersBiso mean: 136.93 Å2
Baniso -1Baniso -2Baniso -3
1-11.5224 Å20 Å20 Å2
2---16.357 Å20 Å2
3---4.8347 Å2
Refine analyzeLuzzati coordinate error obs: 0.63 Å
Refinement stepCycle: 1 / Resolution: 3.8→48.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6721 0 213 0 6934
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0087098HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.019751HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2232SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes115HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1050HARMONIC5
X-RAY DIFFRACTIONt_it7098HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion1.34
X-RAY DIFFRACTIONt_other_torsion19.56
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1031SEMIHARMONIC5
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_contact7482SEMIHARMONIC4
LS refinement shellResolution: 3.8→4.03 Å / Rfactor Rfree error: 0 / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.284 133 5.29 %
Rwork0.267 2379 -
all0.268 2512 -
obs--83.29 %
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)
11.1155-0.4531-0.86573.25362.06522.8008-0.00870.0066-0.14550.3517-0.05020.26230.2468-0.03670.0589-0.48470.14380.0672-0.17690.0757-0.2514-18.6611-20.549615.8347
20.92870.51280.28942.22932.61673.3594-0.0331-0.1364-0.58520.7034-0.08310.24230.7823-0.21770.1162-0.3950.00250.2156-0.41190.1044-0.1499-31.4872-34.320413.2296
32.4124-1.8865-1.18676.48082.29764.53120.24450.33940.2515-1.2246-0.41720.1296-0.946-0.31320.1727-0.51810.22370.0469-0.46280.1203-0.7714-32.685819.685526.1641
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|9 - A|552 A|601 - A|601 }A9 - 552
2X-RAY DIFFRACTION1{ A|9 - A|552 A|601 - A|601 }A601
3X-RAY DIFFRACTION2{ B|59 - B|272 }B59 - 272
4X-RAY DIFFRACTION3{ B|301 - B|301 }B301

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