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- PDB-6c9g: AMP-activated protein kinase bound to pharmacological activator R739 -

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Basic information

Entry
Database: PDB / ID: 6c9g
TitleAMP-activated protein kinase bound to pharmacological activator R739
Components
  • (5'-AMP-activated protein kinase subunit ...) x 2
  • 5'-AMP-activated protein kinase catalytic subunit alpha-1,5'-AMP-activated protein kinase catalytic subunit alpha-1
KeywordsTRANSFERASE / AMPK / activator / crystal / R739
Function / homology
Function and homology information


negative regulation of glucosylceramide biosynthetic process / positive regulation of mitochondrial transcription / [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase / nail development / [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase activity / regulation of stress granule assembly / histone H2BS36 kinase activity / regulation of peptidyl-serine phosphorylation / cold acclimation / positive regulation of peptidyl-lysine acetylation ...negative regulation of glucosylceramide biosynthetic process / positive regulation of mitochondrial transcription / [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase / nail development / [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase activity / regulation of stress granule assembly / histone H2BS36 kinase activity / regulation of peptidyl-serine phosphorylation / cold acclimation / positive regulation of peptidyl-lysine acetylation / bile acid signaling pathway / lipid droplet disassembly / Lipophagy / regulation of bile acid secretion / positive regulation of skeletal muscle tissue development / import into nucleus / CAMKK-AMPK signaling cascade / cAMP-dependent protein kinase regulator activity / regulation of vesicle-mediated transport / positive regulation of cholesterol biosynthetic process / nucleotide-activated protein kinase complex / : / positive regulation of T cell mediated immune response to tumor cell / Energy dependent regulation of mTOR by LKB1-AMPK / tau-protein kinase / negative regulation of hepatocyte apoptotic process / protein kinase regulator activity / cellular response to ethanol / negative regulation of TOR signaling / protein localization to lipid droplet / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / response to caffeine / motor behavior / regulation of glycolytic process / bile acid and bile salt transport / positive regulation of protein targeting to mitochondrion / cAMP-dependent protein kinase activity / lipid biosynthetic process / AMP-activated protein kinase activity / negative regulation of tubulin deacetylation / tau-protein kinase activity / Macroautophagy / cholesterol biosynthetic process / AMP binding / fatty acid oxidation / positive regulation of protein kinase activity / fatty acid homeostasis / negative regulation of lipid catabolic process / cellular response to nutrient levels / regulation of microtubule cytoskeleton organization / positive regulation of autophagy / cellular response to glucose starvation / Activation of AMPK downstream of NMDARs / response to UV / positive regulation of protein localization / energy homeostasis / negative regulation of insulin receptor signaling pathway / negative regulation of TORC1 signaling / positive regulation of adipose tissue development / positive regulation of glycolytic process / cellular response to calcium ion / response to gamma radiation / response to activity / Translocation of SLC2A4 (GLUT4) to the plasma membrane / TP53 Regulates Metabolic Genes / cellular response to glucose stimulus / ADP binding / regulation of circadian rhythm / tau protein binding / Wnt signaling pathway / autophagy / fatty acid biosynthetic process / cellular response to hydrogen peroxide / response to estrogen / neuron cellular homeostasis / glucose metabolic process / cellular response to prostaglandin E stimulus / positive regulation of T cell activation / rhythmic process / cellular response to xenobiotic stimulus / positive regulation of cold-induced thermogenesis / glucose homeostasis / cellular response to oxidative stress / cellular response to hypoxia / spermatogenesis / Regulation of TP53 Activity through Phosphorylation / non-specific serine/threonine protein kinase / response to hypoxia / protein kinase activity / nuclear speck / protein phosphorylation / apical plasma membrane / axon / negative regulation of gene expression / protein serine kinase activity / protein serine/threonine kinase activity / neuronal cell body / chromatin binding / dendrite / positive regulation of cell population proliferation
Similarity search - Function
PRKAA1, UBA-like autoinhibitory domain / 5'-AMP-activated protein kinase alpha 1 catalytic subunit, 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 ...PRKAA1, UBA-like autoinhibitory domain / 5'-AMP-activated protein kinase alpha 1 catalytic subunit, 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 / 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
ADENOSINE MONOPHOSPHATE / Chem-R93 / STAUROSPORINE / 5'-AMP-activated protein kinase subunit gamma-1 / 5'-AMP-activated protein kinase catalytic subunit alpha-1 / 5'-AMP-activated protein kinase subunit beta-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsYan, Y. / Zhou, X.E. / Novick, S. / Shaw, S.J. / Li, Y. / Hitoshi, Y. / Brunzelle, J.S. / Griffin, P.R. / Xu, H.E. / Melcher, K.
Funding support United States, China, 9items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM102545 United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)DK071662 United States
National Natural Science Foundation of China (NSFC)31300245 China
Ministry of Science and Technology (MoST, China)2012ZX09301001 China
Ministry of Science and Technology (MoST, China)2012CB910403 China
Ministry of Science and Technology (MoST, China)2013CB910600 China
Ministry of Science and Technology (MoST, China)XDB08020303 China
Ministry of Science and Technology (MoST, China)2013ZX09507001 China
Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor085P1000817 United States
CitationJournal: J. Biol. Chem. / Year: 2019
Title: Structures of AMP-activated protein kinase bound to novel pharmacological activators in phosphorylated, non-phosphorylated, and nucleotide-free states.
Authors: Yan, Y. / Zhou, X.E. / Novick, S.J. / Shaw, S.J. / Li, Y. / Brunzelle, J.S. / Hitoshi, Y. / Griffin, P.R. / Xu, H.E. / Melcher, K.
History
DepositionJan 26, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 28, 2018Provider: repository / Type: Initial release
Revision 1.1Dec 12, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.pdbx_database_id_DOI ..._citation.journal_abbrev / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Jan 30, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
Revision 1.3Feb 20, 2019Group: Author supporting evidence / Data collection / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Apr 17, 2019Group: Author supporting evidence / Data collection / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.5Dec 25, 2019Group: Author supporting evidence / Database references / Category: pdbx_audit_support / struct_ref_seq_dif
Item: _pdbx_audit_support.funding_organization / _struct_ref_seq_dif.details
Revision 1.6Oct 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

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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-1,5'-AMP-activated protein kinase catalytic subunit alpha-1
B: 5'-AMP-activated protein kinase subunit beta-1
C: 5'-AMP-activated protein kinase subunit gamma-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)119,9378
Polymers117,9433
Non-polymers1,9945
Water93752
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area13830 Å2
ΔGint-72 kcal/mol
Surface area41190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)122.986, 122.986, 406.048
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122

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Components

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Protein , 1 types, 1 molecules A

#1: Protein 5'-AMP-activated protein kinase catalytic subunit alpha-1,5'-AMP-activated protein kinase catalytic subunit alpha-1 / AMPK subunit alpha-1 / Acetyl-CoA carboxylase kinase / ACACA kinase / Hydroxymethylglutaryl-CoA ...AMPK subunit alpha-1 / Acetyl-CoA carboxylase kinase / ACACA kinase / Hydroxymethylglutaryl-CoA reductase kinase / HMGCR kinase / Tau-protein kinase PRKAA1


Mass: 57245.625 Da / Num. of mol.: 1 / Mutation: S108D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRKAA1, AMPK1 / Production host: Escherichia coli (E. coli)
References: UniProt: Q13131, non-specific serine/threonine protein kinase, EC: 2.7.11.27, [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase, tau-protein kinase

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

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


Mass: 23071.316 Da / Num. of mol.: 1
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: 37626.289 Da / Num. of mol.: 1
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 , 4 types, 57 molecules

#4: Chemical ChemComp-R93 / 5-{[6-chloro-5-(2'-hydroxy[1,1'-biphenyl]-4-yl)-1H-benzimidazol-2-yl]oxy}-N-hydroxy-2-methylbenzamide


Mass: 485.918 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H20ClN3O4
#5: Chemical ChemComp-STU / STAUROSPORINE


Mass: 466.531 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H26N4O3 / Comment: anticancer, antifungal, antibiotic, alkaloid*YM
#6: Chemical ChemComp-AMP / ADENOSINE MONOPHOSPHATE


Mass: 347.221 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C10H14N5O7P / Comment: AMP*YM
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 52 / Source method: isolated from a natural source / Formula: H2O

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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: 3.74 Å3/Da / Density % sol: 67.15 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 0.1 M tri-sodium acetate pH 5.6, 0.2 M ammonium acetate, 15% w/v PEG 4000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Nov 11, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.7→50 Å / Num. obs: 51131 / % possible obs: 100 % / Redundancy: 28.3 % / CC1/2: 0.999 / Rmerge(I) obs: 0.181 / Net I/σ(I): 18.7
Reflection shellResolution: 2.7→2.78 Å / Rmerge(I) obs: 0.0238 / Num. unique obs: 4351 / CC1/2: 0.829

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
iMOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4RER

4rer


Resolution: 2.7→49.556 Å / SU ML: 0.31 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 23.92 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2401 3622 7.1 %
Rwork0.2023 --
obs0.2049 51004 99.97 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.7→49.556 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6979 0 139 52 7170
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0067296
X-RAY DIFFRACTIONf_angle_d0.9549909
X-RAY DIFFRACTIONf_dihedral_angle_d12.142761
X-RAY DIFFRACTIONf_chiral_restr0.0381113
X-RAY DIFFRACTIONf_plane_restr0.0051225
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.7-2.79650.29973780.28844630X-RAY DIFFRACTION100
2.7965-2.90850.28913650.27354588X-RAY DIFFRACTION100
2.9085-3.04080.30953650.25914644X-RAY DIFFRACTION100
3.0408-3.20110.29643350.25874667X-RAY DIFFRACTION100
3.2011-3.40160.28853390.24144709X-RAY DIFFRACTION100
3.4016-3.66420.25873220.21444729X-RAY DIFFRACTION100
3.6642-4.03280.22183980.19994674X-RAY DIFFRACTION100
4.0328-4.6160.20363600.16724770X-RAY DIFFRACTION100
4.616-5.81420.21383690.17194835X-RAY DIFFRACTION100
5.8142-49.56480.23043910.18715136X-RAY DIFFRACTION100
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)
10.0009-0.0003-0.00120.00290.00120.0026-0.00750.00620.0067-0.0075-0.01260.0092-0.00140.0174-00.4171-0.09560.02720.4019-0.14880.4575-9.111726.6498-32.5463
20.0010.00130.00080.00240.00020.00080.01810.0033-0.0017-0.0080.0058-0.0043-0.0215-0.015300.46230.0214-0.01830.356-0.12420.306-23.057435.978-30.6398
30.005-0.0060.00040.0152-0.00210.00540.0163-0.0182-0.01880.01780.0093-0.0314-0.04330.01730.0040.34090.0093-0.02140.2701-0.14640.2758-19.267624.9762-16.4354
40.009-0.0043-0.00690.00960.00730.0072-0.00390.0274-0.01870.0008-0.06290.0344-0.0355-0.08610.00090.3590.0453-0.00090.4207-0.18010.2948-36.644720.3373-12.112
50.0018-0.0037-0.0020.00530.00550.0072-0.00430.01140.01390.0264-0.0207-0.01310.0046-0.002400.46940.01780.00490.4313-0.14180.3949-25.675832.35021.3667
60.008-0.01040.00080.01170.0040.00660.02780.04270.031-0.0253-0.01810.0224-0.0566-0.0048-00.97160.4006-0.0760.8566-0.1990.7451-51.975551.1437-15.3552
70.0072-0.0036-00.00420.00250.00610.00140.03180.02490.0249-0.04190.0125-0.0434-0.023100.567-0.0666-0.00840.5122-0.12270.4611-11.444733.7269-51.5599
80.01250.01170.00190.01270.00880.0070.0213-0.0112-0.0162-0.020.02910.0178-0.0327-0.015800.82220.33270.0230.8461-0.20390.7606-43.070447.8418-9.4944
90.0012-0.0008-0.00220.00050.00440.0011-0.01480.0057-0.00720.0039-0.0309-0.0075-0.00570.0123-00.6320.02980.1280.7079-0.08650.7051-23.85459.83185.4792
100.0024-0.00310.00070.0033-0.00270.0023-0.0395-0.00940.024-0.0475-0.0608-0.0283-0.0246-0.037600.65140.22250.11490.5293-0.13220.6146-52.522668.65118.718
110.00090.0008-0.00080.0002-0.00040.0003-0.01710.0054-0.0008-0.01170.0054-0.0133-0.0044-0.001601.0989-0.05340.1231.0801-0.03491.1059-32.229772.61144.1901
12-0.0008-0.001-0.0001-00.0020.00150.0035-0.00910.0040.0056-0.0073-0.0143-0.0090.0114-00.76160.02040.17610.7868-0.09030.853-29.268661.64477.5557
130.00220.00240.00270.00750.00990.00180.0211-0.00470.01020.03150.02990.0119-0.01720.023700.49430.04130.07270.5161-0.13340.7326-33.04270.849829.0344
140.0028-0.0065-0.00190.01010.00490.00220.00120.005-0.02020.01170.002-0.0710.0009-0.0297-00.53090.09590.02350.614-0.0870.8033-43.98661.39528.6072
150.00210.00160.00090.00090.00140.0002-0.00010.0007-0.00960.0117-0.0045-0.0148-0.00530.00500.7003-0.01620.10510.7908-0.15890.9642-26.674465.186126.445
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 11 through 42 )
2X-RAY DIFFRACTION2chain 'A' and (resid 43 through 72 )
3X-RAY DIFFRACTION3chain 'A' and (resid 73 through 162 )
4X-RAY DIFFRACTION4chain 'A' and (resid 163 through 250 )
5X-RAY DIFFRACTION5chain 'A' and (resid 251 through 341 )
6X-RAY DIFFRACTION6chain 'A' and (resid 342 through 549 )
7X-RAY DIFFRACTION7chain 'B' and (resid 74 through 161 )
8X-RAY DIFFRACTION8chain 'B' and (resid 162 through 270 )
9X-RAY DIFFRACTION9chain 'C' and (resid 25 through 48 )
10X-RAY DIFFRACTION10chain 'C' and (resid 49 through 120 )
11X-RAY DIFFRACTION11chain 'C' and (resid 121 through 146 )
12X-RAY DIFFRACTION12chain 'C' and (resid 147 through 181 )
13X-RAY DIFFRACTION13chain 'C' and (resid 182 through 235 )
14X-RAY DIFFRACTION14chain 'C' and (resid 236 through 283 )
15X-RAY DIFFRACTION15chain 'C' and (resid 284 through 324 )

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