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- PDB-7myj: Structure of full length human AMPK (a2b1g1) in complex with a sm... -

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Basic information

Entry
Database: PDB / ID: 7myj
TitleStructure of full length human AMPK (a2b1g1) in complex with a small molecule activator MSG011
Components
  • (5'-AMP-activated protein kinase subunit ...) x 2
  • 5'-AMP-activated protein kinase catalytic subunit alpha-2
KeywordsSIGNALING PROTEIN / Activator / Kinase / AMPK
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 / protein phosphorylation / negative regulation of gene expression / 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 / : / 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
Chem-4O7 / ADENOSINE MONOPHOSPHATE / Chem-ZQV / 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: 2.95 Å
AuthorsOvens, A.J. / Gee, Y.S. / Ling, N.X.Y. / Waters, N.J. / Yu, D. / Scott, J.W. / Parker, M.W. / Hoffman, N.J. / Kemp, B.E. / Baell, J.B. ...Ovens, A.J. / Gee, Y.S. / Ling, N.X.Y. / Waters, N.J. / Yu, D. / Scott, J.W. / Parker, M.W. / Hoffman, N.J. / Kemp, B.E. / Baell, J.B. / Oakhill, J.S. / Langendorf, C.G.
Funding support Australia, 5items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)GNT1143080 Australia
National Health and Medical Research Council (NHMRC, Australia)1098459 Australia
National Health and Medical Research Council (NHMRC, Australia)1145265 Australia
National Health and Medical Research Council (NHMRC, Australia)1138102 Australia
Australian Research Council (ARC)DP170101196 Australia
CitationJournal: Biochem.J. / Year: 2022
Title: Structure-function analysis of the AMPK activator SC4 and identification of a potent pan AMPK activator.
Authors: Ovens, A.J. / Gee, Y.S. / Ling, N.X.Y. / Yu, D. / Hardee, J.P. / Chung, J.D. / Ngoei, K.R.W. / Waters, N.J. / Hoffman, N.J. / Scott, J.W. / Loh, K. / Spengler, K. / Heller, R. / Parker, M.W. ...Authors: Ovens, A.J. / Gee, Y.S. / Ling, N.X.Y. / Yu, D. / Hardee, J.P. / Chung, J.D. / Ngoei, K.R.W. / Waters, N.J. / Hoffman, N.J. / Scott, J.W. / Loh, K. / Spengler, K. / Heller, R. / Parker, M.W. / Lynch, G.S. / Huang, F. / Galic, S. / Kemp, B.E. / Baell, J.B. / Oakhill, J.S. / Langendorf, C.G.
History
DepositionMay 21, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 29, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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
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)268,66014
Polymers265,2976
Non-polymers3,3648
Water00
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)134,3307
Polymers132,6483
Non-polymers1,6824
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area15530 Å2
ΔGint-103 kcal/mol
Surface area41370 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)134,3307
Polymers132,6483
Non-polymers1,6824
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area15220 Å2
ΔGint-105 kcal/mol
Surface area43390 Å2
MethodPISA
Unit cell
Length a, b, c (Å)75.844, 134.199, 141.821
Angle α, β, γ (deg.)90.00, 92.55, 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 / Mutation: D271G
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRKAA2, AMPK, AMPK2 / Production host: Escherichia coli (E. coli)
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 / Production host: Escherichia coli (E. coli) / 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 / Production host: Escherichia coli (E. coli) / References: UniProt: P54619

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Non-polymers , 3 types, 8 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-ZQV / 5-({5-[(4'R)-4'-acetamido-2',3',4',5'-tetrahydro[1,1'-biphenyl]-4-yl]-6-chloro-1H-imidazo[4,5-b]pyridin-2-yl}oxy)-2-methylbenzoic acid


Mass: 516.976 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H25ClN4O4 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical
ChemComp-AMP / ADENOSINE MONOPHOSPHATE


Mass: 347.221 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H14N5O7P / Comment: AMP*YM

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Details

Has ligand of interestY

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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: 54.74 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / pH: 6.2
Details: 8-10% PEG3350, 1% glucose, 0.1 M magnesium chloride, 0.1 M imidazole, 0.0005-0.003% CAPB

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.71073 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 2, 2019
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.71073 Å / Relative weight: 1
ReflectionResolution: 2.95→48.72 Å / Num. obs: 59194 / % possible obs: 98.91 % / Redundancy: 2.4 % / Biso Wilson estimate: 70.8 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.053 / Rpim(I) all: 0.053 / Rrim(I) all: 0.075 / Net I/σ(I): 10.7
Reflection shellResolution: 2.95→3.055 Å / Redundancy: 2.2 % / Rmerge(I) obs: 0.37 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 5846 / CC1/2: 0.735 / Rpim(I) all: 0.369 / Rrim(I) all: 0.523 / % possible all: 97.82

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Processing

Software
NameVersionClassification
BUSTER2.10.2refinement
Cootmodel building
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 6B1U

6b1u


Resolution: 2.95→48.72 Å / Cor.coef. Fo:Fc: 0.919 / Cor.coef. Fo:Fc free: 0.906 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 9.338 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 1.277 / SU Rfree Blow DPI: 0.342 / SU Rfree Cruickshank DPI: 0.358
RfactorNum. reflection% reflectionSelection details
Rfree0.243 2991 5.05 %RANDOM
Rwork0.213 ---
obs0.215 59183 99 %-
Displacement parametersBiso mean: 76.11 Å2
Baniso -1Baniso -2Baniso -3
1-5.6837 Å20 Å2-7.3348 Å2
2---9.7421 Å20 Å2
3---4.0584 Å2
Refine analyzeLuzzati coordinate error obs: 0.42 Å
Refinement stepCycle: LAST / Resolution: 2.95→48.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14501 0 277 0 14778
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00815159HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.9820694HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d4973SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes292HARMONIC2
X-RAY DIFFRACTIONt_gen_planes2202HARMONIC5
X-RAY DIFFRACTIONt_it15159HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion1.83
X-RAY DIFFRACTIONt_other_torsion17.33
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion2006SEMIHARMONIC5
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_contact16393SEMIHARMONIC4
LS refinement shellResolution: 2.95→3.03 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.308 217 4.97 %
Rwork0.266 4149 -
all0.269 4366 -
obs--98.1 %
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)
12.0087-1.3379-1.13591.58690.80151.0284-0.1304-0.20680.00680.15580.12390.06980.20730.2290.0065-0.00750.019-0.04280.14570.04030.10021.8738-14.2233-48.4696
22.6476-2.238-2.31851.82672.08522.5436-0.7514-0.2221-0.41240.66830.34590.49530.88980.21370.40550.2366-0.02260.1461-0.01720.05460.02640.2227-31.6731-51.7308
31.4210.79630.6231.03570.55291.1763-0.22250.30110.0209-0.27380.2758-0.0695-0.29090.2246-0.05330.1123-0.12570.04070.0304-0.00370.0967-35.8075-61.6856-20.3315
41.02071.7391.02142.66262.17341.2551-0.31230.26080.0633-0.43440.4248-0.0411-0.39350.1995-0.11250.2256-0.1017-0.09090.0320.03580.0172-36.5-43.9974-18.2095
52.5941-0.842-1.9072.20330.60032.57050.11480.26460.1224-0.1026-0.00450.1351-0.261-0.3252-0.11040.1079-0.04050.0140.1544-0.0030.1452-32.47649.8465-37.3654
61.82150.28430.75371.06950.42412.9568-0.10030.2028-0.1521-0.04610.10130.20650.1392-0.4052-0.00090.0764-0.0856-0.02560.1305-0.0080.0996-70.0928-83.8522-35.0197
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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