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- PDB-4zhx: Novel binding site for allosteric activation of AMPK -

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Basic information

Entry
Database: PDB / ID: 4zhx
TitleNovel binding site for allosteric activation of AMPK
Components
  • (5'-AMP-activated protein kinase subunit ...) x 2
  • 5'-AMP-activated protein kinase catalytic subunit alpha-2
KeywordsTRANSFERASE / serine/threonine kinase / allosteric activation / nucleotide-binding
Function / homology
Function and homology information


[hydroxymethylglutaryl-CoA reductase (NADPH)] kinase / nail development / [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 ...[hydroxymethylglutaryl-CoA reductase (NADPH)] kinase / nail development / [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 / nucleotide-activated protein kinase complex / Energy dependent regulation of mTOR by LKB1-AMPK / Carnitine metabolism / negative regulation of hepatocyte apoptotic process / protein kinase regulator activity / protein localization to lipid droplet / negative regulation of TOR signaling / response to muscle activity / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / regulation of glycolytic process / Nuclear events mediated by NFE2L2 / lipid biosynthetic process / cAMP-dependent protein kinase activity / AMP-activated protein kinase activity / negative regulation of tubulin deacetylation / Macroautophagy / positive regulation of protein localization / AMP binding / cholesterol biosynthetic process / cellular response to nutrient levels / positive regulation of macroautophagy / positive regulation of protein kinase activity / regulation of macroautophagy / fatty acid homeostasis / cellular response to glucose starvation / positive regulation of autophagy / energy homeostasis / regulation of microtubule cytoskeleton organization / Activation of AMPK downstream of NMDARs / 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 / ADP binding / Wnt signaling pathway / fatty acid biosynthetic process / autophagy / cytoplasmic stress granule / cellular response to prostaglandin E stimulus / rhythmic process / cellular response to xenobiotic stimulus / glucose homeostasis / positive regulation of cold-induced thermogenesis / cellular response to oxidative stress / 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 / neuronal cell body / chromatin binding / dendrite / positive regulation of gene expression / negative regulation of apoptotic process / protein kinase binding / Golgi apparatus / signal transduction / nucleoplasm / ATP binding / membrane / nucleus / metal ion binding / cytoplasm / cytosol
Similarity search - Function
PRKAA2, UBA-like autoinhibitory domain / 5'-AMP-activated protein kinase catalytic subunit alpha-2, C-terminal / Kinase associated domain 1, KA1 / : / 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 ...PRKAA2, UBA-like autoinhibitory domain / 5'-AMP-activated protein kinase catalytic subunit alpha-2, C-terminal / Kinase associated domain 1, KA1 / : / 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 / TATA-Binding Protein / CBS domain superfamily / Domain in cystathionine beta-synthase and other proteins. / CBS domain / CBS domain / CBS domain profile. / Immunoglobulin E-set / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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 / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-4O7 / ADENOSINE MONOPHOSPHATE / Chem-C1V / Chem-C2Z / 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: 2.99 Å
AuthorsLangendorf, C.G. / Ngoei, K.R. / Issa, S.M.A. / Ling, N. / Gorman, M.A. / Parker, M.W. / Sakamoto, K. / Scott, J.W. / Oakhill, J.S. / Kemp, B.E.
CitationJournal: Nat Commun / Year: 2016
Title: Structural basis of allosteric and synergistic activation of AMPK by furan-2-phosphonic derivative C2 binding.
Authors: Langendorf, C.G. / Ngoei, K.R. / Scott, J.W. / Ling, N.X. / Issa, S.M. / Gorman, M.A. / Parker, M.W. / Sakamoto, K. / Oakhill, J.S. / Kemp, B.E.
History
DepositionApr 27, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 9, 2016Provider: repository / Type: Initial release
Revision 1.1Mar 23, 2016Group: Database references
Revision 1.2Sep 27, 2017Group: Author supporting evidence / Data collection / Derived calculations
Category: diffrn_source / pdbx_audit_support / pdbx_struct_oper_list
Item: _diffrn_source.pdbx_synchrotron_site / _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_entity_nonpoly / pdbx_initial_refinement_model
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.name

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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)268,11514
Polymers265,2976
Non-polymers2,8198
Water2,468137
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)133,9417
Polymers132,6483
Non-polymers1,2934
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11240 Å2
ΔGint-69 kcal/mol
Surface area41730 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)134,1747
Polymers132,6483
Non-polymers1,5254
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area15200 Å2
ΔGint-91 kcal/mol
Surface area42860 Å2
MethodPISA
Unit cell
Length a, b, c (Å)75.950, 134.240, 141.480
Angle α, β, γ (deg.)90.000, 93.020, 90.000
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 2 (DE3)
References: UniProt: P54646, non-specific serine/threonine protein kinase, [acetyl-CoA carboxylase] kinase, [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: RSFDuet-1 / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta 2 (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 2 (DE3) / References: UniProt: P54619

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Non-polymers , 5 types, 145 molecules

#4: Chemical ChemComp-4O7 / (5S,6R,7R,9R,13cR,14R,16aS)-6-methoxy-5-methyl-7-(methylamino)-6,7,8,9,14,15,16,16a-octahydro-5H,13cH-5,9-epoxy-4b,9a,1 5-triazadibenzo[b,h]cyclonona[1,2,3,4-jkl]cyclopenta[e]-as-indacen-14-ol / staurosporine


Mass: 470.563 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H30N4O3 / Comment: anticancer, antifungal, antibiotic, alkaloid*YM
#5: Chemical ChemComp-C1V / 3-[4-(2-hydroxyphenyl)phenyl]-4-oxidanyl-6-oxidanylidene-7H-thieno[2,3-b]pyridine-5-carbonitrile


Mass: 360.386 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H12N2O3S
#6: Chemical ChemComp-C2Z / 5-(5-hydroxyl-isoxazol-3-yl)-furan-2-phosphonic acid / [5-(5-hydroxy-1,2-oxazol-3-yl)furan-2-yl]phosphonic acid


Mass: 231.099 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C7H6NO6P
#7: Chemical ChemComp-AMP / ADENOSINE MONOPHOSPHATE


Mass: 347.221 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H14N5O7P / Comment: AMP*YM
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 137 / Source method: isolated from a natural source / Formula: H2O

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Details

Sequence detailsThe D271G variant has been previously reported and can be found in the uniprot entry for AMPK alpha- ...The D271G variant has been previously reported and can be found in the uniprot entry for AMPK alpha-2 (P54646 - AAPK2_HUMAN) in the experimental info section.

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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: 2.72 Å3/Da / Density % sol: 54.75 %
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, 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: Feb 6, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 2.99→48.66 Å / Num. obs: 56598 / % possible obs: 98.8 % / Redundancy: 3.2 % / Biso Wilson estimate: 83.79 Å2 / CC1/2: 0.976 / Rmerge(I) obs: 0.107 / Rpim(I) all: 0.071 / Net I/σ(I): 8.1 / Num. measured all: 183106 / Scaling rejects: 229
Reflection shell

Diffraction-ID: 1 / Redundancy: 3.2 % / Rejects: _

Resolution (Å)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allCC1/2Rpim(I) all% possible all
2.99-3.080.7142.21516646880.5570.47999.4
12.69-48.660.0516.723847390.9830.03395.7

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Processing

Software
NameVersionClassification
BUSTER-TNT2.10.0refinement
Aimless0.1.27data scaling
PDB_EXTRACT3.15data extraction
XDSNovember 2014data reduction
PHASER6.3.0phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4CFE

4cfe


Resolution: 2.99→43.78 Å / Cor.coef. Fo:Fc: 0.8851 / Cor.coef. Fo:Fc free: 0.8649 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.359
RfactorNum. reflection% reflectionSelection details
Rfree0.243 2867 5.07 %RANDOM
Rwork0.2252 ---
obs0.2262 56564 98.59 %-
Displacement parametersBiso max: 229.33 Å2 / Biso mean: 69.7 Å2 / Biso min: 14.97 Å2
Baniso -1Baniso -2Baniso -3
1-4.0703 Å20 Å2-0.1024 Å2
2---14.9803 Å20 Å2
3---10.91 Å2
Refine analyzeLuzzati coordinate error obs: 0.504 Å
Refinement stepCycle: final / Resolution: 2.99→43.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14236 0 198 137 14571
Biso mean--56.32 41.86 -
Num. residues----1807
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d5206SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes314HARMONIC2
X-RAY DIFFRACTIONt_gen_planes2175HARMONIC5
X-RAY DIFFRACTIONt_it15098HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1953SEMIHARMONIC5
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_contact16096SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d15098HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg20517HARMONIC20.95
X-RAY DIFFRACTIONt_omega_torsion1.43
X-RAY DIFFRACTIONt_other_torsion19.09
LS refinement shellResolution: 2.99→3.07 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2588 202 4.81 %
Rwork0.2574 3994 -
all0.2574 4196 -
obs--98.59 %
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)
12.3854-1.4765-1.56471.59610.6981.442-0.098-0.10550.0410.16680.149-0.00220.17710.2544-0.051-0.10930.0147-0.0179-0.0230.01610.0246113.4022-11.932923.6376
22.3213-2.2783-1.86512.77291.94682.5134-0.0971-0.0019-0.0631-0.00970.1160.16510.2652-0.0725-0.01880.1356-0.06370.0561-0.066-0.0090.0716111.3796-28.963216.9903
31.49640.8060.87071.04580.49991.4554-0.22870.310.0656-0.22050.2767-0.0513-0.31440.2879-0.0480.1134-0.12320.12770.02630.00210.1279151.2816-58.918749.3216
40.98261.63690.9472.55631.88541.2923-0.07750.230.0386-0.24150.16680.0657-0.1605-0.0832-0.08930.0323-0.04670.0155-0.18130.05250.0054148.8218-41.542454.0181
52.0363-0.7228-1.46712.02670.40632.4597-0.00230.23430.1096-0.07150.010.0991-0.233-0.295-0.0078-0.0385-0.00560.0628-0.04540.03380.057477.818212.864533.4166
61.89230.55891.24261.61060.05983.2128-0.08210.2249-0.1647-0.06550.13580.22050.1739-0.257-0.0537-0.0012-0.050.0745-0.0380.03660.0095115.7344-81.868335.3685
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A9 - 728
2X-RAY DIFFRACTION2{ B|* }B78 - 413
3X-RAY DIFFRACTION3{ C|* }C9 - 733
4X-RAY DIFFRACTION4{ D|* }D78 - 316
5X-RAY DIFFRACTION5{ E|* }E27 - 526
6X-RAY DIFFRACTION6{ F|* }F26 - 521

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