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- PDB-6cmj: Human CAMKK2 with GSK650393 -

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Basic information

Entry
Database: PDB / ID: 6cmj
TitleHuman CAMKK2 with GSK650393
ComponentsCalcium/calmodulin-dependent protein kinase kinase 2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase / signaling protein / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


positive regulation of autophagy of mitochondrion / Ca2+/calmodulin-dependent protein kinase / CAMKK-AMPK signaling cascade / regulation of protein kinase activity / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / calmodulin-dependent protein kinase activity / CaMK IV-mediated phosphorylation of CREB / Activation of RAC1 downstream of NMDARs / Activation of AMPK downstream of NMDARs / calcium-mediated signaling ...positive regulation of autophagy of mitochondrion / Ca2+/calmodulin-dependent protein kinase / CAMKK-AMPK signaling cascade / regulation of protein kinase activity / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / calmodulin-dependent protein kinase activity / CaMK IV-mediated phosphorylation of CREB / Activation of RAC1 downstream of NMDARs / Activation of AMPK downstream of NMDARs / calcium-mediated signaling / cellular response to reactive oxygen species / MAPK cascade / protein tyrosine kinase activity / protein autophosphorylation / calmodulin binding / neuron projection / positive regulation of protein phosphorylation / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / calcium ion binding / positive regulation of DNA-templated transcription / nucleoplasm / ATP binding / cytosol
Similarity search - Function
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
Chem-F6J / FORMIC ACID / Calcium/calmodulin-dependent protein kinase kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsWilliams, S.P. / Reid, R.A. / Price, D.J. / Drewry, D.H.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2018
Title: An orally available, brain-penetrant CAMKK2 inhibitor reduces food intake in rodent model.
Authors: Price, D.J. / Drewry, D.H. / Schaller, L.T. / Thompson, B.D. / Reid, P.R. / Maloney, P.R. / Liang, X. / Banker, P. / Buckholz, R.G. / Selley, P.K. / McDonald, O.B. / Smith, J.L. / Shearer, T. ...Authors: Price, D.J. / Drewry, D.H. / Schaller, L.T. / Thompson, B.D. / Reid, P.R. / Maloney, P.R. / Liang, X. / Banker, P. / Buckholz, R.G. / Selley, P.K. / McDonald, O.B. / Smith, J.L. / Shearer, T.W. / Cox, R.F. / Williams, S.P. / Reid, R.A. / Tacconi, S. / Faggioni, F. / Piubelli, C. / Sartori, I. / Tessari, M. / Wang, T.Y.
History
DepositionMar 5, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 4, 2018Provider: repository / Type: Initial release
Revision 1.1Apr 25, 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.name
Revision 1.2May 16, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Calcium/calmodulin-dependent protein kinase kinase 2
B: Calcium/calmodulin-dependent protein kinase kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,62813
Polymers73,4252
Non-polymers1,20311
Water4,125229
1
A: Calcium/calmodulin-dependent protein kinase kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,2836
Polymers36,7131
Non-polymers5715
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area510 Å2
ΔGint-1 kcal/mol
Surface area14120 Å2
MethodPISA
2
B: Calcium/calmodulin-dependent protein kinase kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,3457
Polymers36,7131
Non-polymers6336
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1050 Å2
ΔGint6 kcal/mol
Surface area13830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)89.841, 89.841, 181.385
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1010A161 - 461
2010B161 - 461

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Components

#1: Protein Calcium/calmodulin-dependent protein kinase kinase 2 / CaMKK 2 / Calcium/calmodulin-dependent protein kinase kinase beta / CaMKK beta


Mass: 36712.598 Da / Num. of mol.: 2 / Fragment: UNP residues 149-465
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CAMKK2, CAMKKB, KIAA0787 / Plasmid: pET24 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q96RR4, Ca2+/calmodulin-dependent protein kinase
#2: Chemical ChemComp-F6J / 2-(2-methylpropyl)-4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid


Mass: 370.444 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H22N2O2
#3: Chemical
ChemComp-FMT / FORMIC ACID


Mass: 46.025 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: CH2O2
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 229 / 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: 2.88 Å3/Da / Density % sol: 57.26 % / Description: Hexagonal rods
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 4 M sodium formate, 3% PEG8000, 20 mM ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Aug 8, 2007 / Details: monochromator
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.39→50 Å / Num. obs: 33208 / % possible obs: 96.2 % / Redundancy: 8.1 % / Biso Wilson estimate: 35.7 Å2 / Rmerge(I) obs: 0.061 / Χ2: 1.352 / Net I/av σ(I): 39.4 / Net I/σ(I): 12.6
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
2.39-2.487.30.31124840.877173.2
2.48-2.5780.26833130.958197.4
2.57-2.697.90.23432811.196197.1
2.69-2.837.90.14433540.993198.3
2.83-3.017.90.10733581.125198.6
3.01-3.247.90.08234051.284199
3.24-3.5780.06834201.706199.3
3.57-4.098.20.05534591.97199.9
4.09-5.158.80.0434821.642199.8
5.15-508.40.03536521.487198.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0189refinement
DENZOdata reduction
HKL-2000data scaling
PDB_EXTRACT3.24data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.4→27.97 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.934 / SU B: 6.662 / SU ML: 0.152 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.295 / ESU R Free: 0.216 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2192 2334 7 %RANDOM
Rwork0.1819 ---
obs0.1845 30817 98.14 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 110 Å2 / Biso mean: 43.869 Å2 / Biso min: 23.07 Å2
Baniso -1Baniso -2Baniso -3
1-1.05 Å20.53 Å20 Å2
2--1.05 Å2-0 Å2
3----3.41 Å2
Refinement stepCycle: final / Resolution: 2.4→27.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4540 0 86 229 4855
Biso mean--38.93 43.9 -
Num. residues----575
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0194730
X-RAY DIFFRACTIONr_bond_other_d0.0020.024342
X-RAY DIFFRACTIONr_angle_refined_deg1.5212.0016408
X-RAY DIFFRACTIONr_angle_other_deg0.958310127
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.9995573
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.90425.673208
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.55315803
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.4891513
X-RAY DIFFRACTIONr_chiral_restr0.0850.2701
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0215246
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02891
Refine LS restraints NCS

Ens-ID: 1 / Number: 18070 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.08 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.404→2.466 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.271 161 -
Rwork0.233 2085 -
all-2246 -
obs--91.86 %

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