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- PDB-9ic2: Structure of AMPK-alpha2-kinase domain bound to BAY-3827 -

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Basic information

Entry
Database: PDB / ID: 9ic2
TitleStructure of AMPK-alpha2-kinase domain bound to BAY-3827
Components5'-AMP-activated protein kinase catalytic subunit alpha-2
KeywordsSIGNALING PROTEIN / Kinase
Function / homology
Function and homology information


[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 / AMP-activated protein kinase activity / lipid droplet disassembly / Lipophagy / nucleotide-activated protein kinase complex / negative regulation of hepatocyte apoptotic process ...[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 / AMP-activated protein kinase activity / lipid droplet disassembly / Lipophagy / nucleotide-activated protein kinase complex / negative regulation of hepatocyte apoptotic process / Carnitine shuttle / Energy dependent regulation of mTOR by LKB1-AMPK / negative regulation of TOR signaling / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / Nuclear events mediated by NFE2L2 / protein localization to lipid droplet / negative regulation of tubulin deacetylation / cholesterol biosynthetic process / Macroautophagy / lipid biosynthetic process / response to muscle 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 autophagy / protein serine/threonine/tyrosine kinase activity / 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 / autophagy / Wnt signaling pathway / cellular response to xenobiotic stimulus / cytoplasmic stress granule / fatty acid biosynthetic process / rhythmic process / cellular response to prostaglandin E stimulus / glucose homeostasis / cellular response to oxidative stress / Regulation of TP53 Activity through Phosphorylation / protein phosphorylation / non-specific serine/threonine protein kinase / protein kinase activity / 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 / negative regulation of apoptotic process / Golgi apparatus / signal transduction / nucleoplasm / ATP binding / 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 / AMPK, C-terminal adenylate sensor domain / Adenylate sensor of SNF1-like protein kinase / KA1 domain/Ssp2, C-terminal / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase 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 / AMPK, C-terminal adenylate sensor domain / Adenylate sensor of SNF1-like protein kinase / KA1 domain/Ssp2, C-terminal / 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. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
: / 5'-AMP-activated protein kinase catalytic subunit alpha-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsAhangar, M.S. / Zeqiraj, E. / Fraguas Bringas, C. / Sakamoto, K.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Wellcome Trust United Kingdom
CitationJournal: To Be Published
Title: Structure of AMPK-alpha2-kinase domain bound to BAY-3827
Authors: Ahangar, M.S. / Zeqiraj, E.
History
DepositionFeb 14, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 3, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: 5'-AMP-activated protein kinase catalytic subunit alpha-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,2236
Polymers31,5861
Non-polymers6385
Water1,11762
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area320 Å2
ΔGint-24 kcal/mol
Surface area12940 Å2
Unit cell
Length a, b, c (Å)59.176, 117.778, 38.327
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Space group name HallP22ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x+1/2,y+1/2,-z
#4: -x,-y,z
Components on special symmetry positions
IDModelComponents
11A-436-

HOH

21A-451-

HOH

31A-452-

HOH

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Components

#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: 31585.754 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: The protein sequence contain first amino acid Gly from the Tev site followed by AMPK-alpha2 (6-280 amino acids). The second amino acid Lys in the protein chain is assigned residue number 6 ...Details: The protein sequence contain first amino acid Gly from the Tev site followed by AMPK-alpha2 (6-280 amino acids). The second amino acid Lys in the protein chain is assigned residue number 6 matching with the actual protein sequence.
Source: (gene. exp.) Homo sapiens (human) / Gene: PRKAA2, AMPK, AMPK2 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P54646, non-specific serine/threonine protein kinase, [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase
#2: Chemical ChemComp-A1I1Y / ~{N}-[5-(3,5-dicyano-1,2,6-trimethyl-4~{H}-pyridin-4-yl)-6-fluoranyl-7-methyl-1~{H}-indazol-3-yl]-2-ethyl-benzamide


Mass: 468.525 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H25FN6O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 62 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
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: 2.11 Å3/Da / Density % sol: 41.82 %
Crystal growTemperature: 295 K / Method: vapor diffusion
Details: 0.1M Ammonium sulfate, 0.3 Sodium formate, 0.1M Sodium cacodylate pH 6.5, 3% Gamma-PGA, 3% PEG 20000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.6199 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 10, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.6199 Å / Relative weight: 1
ReflectionResolution: 2.5→58.89 Å / Num. obs: 10021 / % possible obs: 99.9 % / Redundancy: 6.5 % / Biso Wilson estimate: 39.04 Å2 / CC1/2: 0.997 / CC star: 0.999 / Rmerge(I) obs: 0.074 / Rrim(I) all: 0.081 / Net I/σ(I): 15.7
Reflection shellResolution: 2.5→2.56 Å / Num. unique obs: 890 / CC1/2: 0.944

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Processing

Software
NameVersionClassification
PHENIX1.21.1_5286refinement
autoPROCdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→58.89 Å / SU ML: 0.2577 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 23.7515
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.235 497 5.07 %
Rwork0.1975 9302 -
obs0.1994 9799 99.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 52.63 Å2
Refinement stepCycle: LAST / Resolution: 2.5→58.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2115 0 43 62 2220
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00192219
X-RAY DIFFRACTIONf_angle_d0.47633007
X-RAY DIFFRACTIONf_chiral_restr0.0438327
X-RAY DIFFRACTIONf_plane_restr0.0038384
X-RAY DIFFRACTIONf_dihedral_angle_d12.9076811
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5-2.750.30531190.24332278X-RAY DIFFRACTION100
2.75-3.150.25491410.22552251X-RAY DIFFRACTION100
3.15-3.970.24171130.19472326X-RAY DIFFRACTION99.96
3.97-58.890.20461240.17692447X-RAY DIFFRACTION99.88
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)
10.775817958450.02266062617171.669311640.579015003063-0.6688079533954.45774652832-0.188731300706-0.4800320721470.623745189020.1073250315490.1885030188250.404110052819-0.711439050822-0.7143345885580.1518366463790.689787413585-0.07998335994980.005023053212930.5037353703-0.07419264594230.409392666876-16.214774155318.80213422375.88186791736
22.361382597881.310134368181.480678825465.364981437110.5604604452422.642579330210.196465444395-0.233508479009-0.257261316850.340402699361-0.192092063177-1.059960459340.1036680204220.122556019507-0.03072988564320.158916235673-0.00862024656802-0.05665331243320.3225365142040.03683754946790.357354129999-15.05633952714.199818771132.10731973783
34.622909901521.149339203920.8894474659914.847046803492.99392823883.434025224290.02478833757160.09210006353750.1986918716590.124337616620.0453622612462-0.03258862307380.0189897168955-0.09731105994110.03444269917520.422439977012-0.0722767901484-0.05908520704020.2526307227560.06668779468330.409287473357-16.723457330537.3648162267-7.08966943671
41.880257504891.68021773611-0.3422541651678.37315960555-0.6359208686050.534164034804-0.1986219106520.171368293818-0.146852521805-0.4259840182350.154240050065-0.553540727081-0.08350295905280.00813128471950.07596737512840.281449448102-0.046965569030.04634383427360.3260425137030.02304619892320.208893134596-16.0578289419.6733782191-7.73245368145
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 153 through 192 )153 - 192146 - 180
22chain 'A' and (resid 193 through 279 )193 - 279181 - 267
33chain 'A' and (resid 8 through 70 )8 - 701 - 63
44chain 'A' and (resid 71 through 152 )71 - 15264 - 145

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