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- PDB-8tuc: Unphosphorylated CaMKK2 in complex with CC-8977 -

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Basic information

Entry
Database: PDB / ID: 8tuc
TitleUnphosphorylated CaMKK2 in complex with CC-8977
ComponentsCalcium/calmodulin-dependent protein kinase kinase 2
KeywordsTRANSFERASE/INHIBITOR / Calcium/Calmodulin Dependent Protein Kinase Kinase 2 / CAMKK2 / Inhibitor / 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 / calcium/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 / calcium/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-O7I / Calcium/calmodulin-dependent protein kinase kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 Å
AuthorsBernard, S.M. / Shanmugasundaram, V. / D'Agostino, L.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2023
Title: Identification of Small Molecule Inhibitors and Ligand Directed Degraders of Calcium/Calmodulin Dependent Protein Kinase Kinase 1 and 2 (CaMKK1/2).
Authors: Chen, Y. / Whitefield, B. / Nevius, E. / Hill, M. / DelRosario, J. / Sinitsyna, N. / Shanmugasundaram, V. / Mukherjee, D. / Shi, L. / Mayne, C.G. / Rousseau, A.M. / Bernard, S.M. / ...Authors: Chen, Y. / Whitefield, B. / Nevius, E. / Hill, M. / DelRosario, J. / Sinitsyna, N. / Shanmugasundaram, V. / Mukherjee, D. / Shi, L. / Mayne, C.G. / Rousseau, A.M. / Bernard, S.M. / Buenviaje, J. / Khambatta, G. / El Samin, M. / Wallace, M. / Nie, Z. / Sivakumar, P. / Hamann, L.G. / McDonnell, D.P. / D'Agostino, L.A.
History
DepositionAug 16, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 13, 2023Provider: repository / Type: Initial release
Revision 1.1Dec 27, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,9988
Polymers33,1271
Non-polymers8717
Water5,729318
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)73.108, 73.108, 120.102
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212

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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: 33127.250 Da / Num. of mol.: 1 / Fragment: residues 161-449
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CAMKK2, CAMKKB, KIAA0787 / Production host: Escherichia coli (E. coli)
References: UniProt: Q96RR4, Ca2+/calmodulin-dependent protein kinase
#2: Chemical ChemComp-O7I / (4M)-2-cyclopentyl-4-(7-ethoxyquinazolin-4-yl)benzoic acid


Mass: 362.422 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H22N2O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 318 / Source method: isolated from a natural source / Formula: H2O
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: 2.62 Å3/Da / Density % sol: 49.22 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: 2.0 M (NH4)2S04, 2 M NaCl, 0.1 NaCacodylate

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Data collection

DiffractionMean temperature: 193 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.97741 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: May 19, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97741 Å / Relative weight: 1
ReflectionResolution: 1.5→62.45 Å / Num. obs: 52660 / % possible obs: 99.9 % / Redundancy: 20 % / CC1/2: 1 / Net I/σ(I): 21.4
Reflection shellResolution: 1.5→8.23 Å / Num. unique obs: 407 / CC1/2: 1

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Processing

Software
NameVersionClassification
REFMAC5.8.0218refinement
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.5→62.45 Å / Cor.coef. Fo:Fc: 0.972 / Cor.coef. Fo:Fc free: 0.959 / SU B: 2.967 / SU ML: 0.053 / Cross valid method: THROUGHOUT / ESU R: 0.066 / ESU R Free: 0.072 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20678 2680 5.1 %RANDOM
Rwork0.16692 ---
obs0.1689 49899 99.92 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 25.645 Å2
Baniso -1Baniso -2Baniso -3
1--0.13 Å20 Å20 Å2
2---0.13 Å20 Å2
3---0.26 Å2
Refinement stepCycle: 1 / Resolution: 1.5→62.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2231 0 55 318 2604
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0240.0192345
X-RAY DIFFRACTIONr_bond_other_d0.0010.022203
X-RAY DIFFRACTIONr_angle_refined_deg2.1191.9773172
X-RAY DIFFRACTIONr_angle_other_deg0.9712.9945111
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.895280
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.91524.952105
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.8815421
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.1221510
X-RAY DIFFRACTIONr_chiral_restr0.1490.2349
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.0212518
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02433
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.6621.8881114
X-RAY DIFFRACTIONr_mcbond_other1.6631.8851113
X-RAY DIFFRACTIONr_mcangle_it2.4692.8231390
X-RAY DIFFRACTIONr_mcangle_other2.4682.8261391
X-RAY DIFFRACTIONr_scbond_it2.9462.2281230
X-RAY DIFFRACTIONr_scbond_other2.9452.2281230
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.0893.231781
X-RAY DIFFRACTIONr_long_range_B_refined6.03624.2892780
X-RAY DIFFRACTIONr_long_range_B_other6.03524.3082781
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.502→1.541 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.313 184 -
Rwork0.304 3621 -
obs--99.32 %
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)
10.8262-0.364-0.05991.14-0.63460.4507-0.0547-0.018-0.01330.04260.0127-0.0572-0.0059-0.00380.0420.0379-0.0026-0.01160.03420.01590.014417.016-33.76121.546
21.9488-0.7284-1.10481.3951.65872.01430.0635-0.22530.11090.1725-0.1620.0980.1907-0.13140.09850.0636-0.04380.04230.1188-0.02510.03671.646-25.34131.874
30.03080.09580.07920.32160.28950.31980.0095-0.00740.03420.0422-0.06820.08830.0892-0.10450.05870.052-0.0354-0.00180.09980.01810.0579-3.436-23.9320.631
40.50940.24820.32620.7784-0.15970.37770.0764-0.0208-0.0591-0.0187-0.04140.01460.0786-0.0076-0.0350.0297-0.0122-0.00940.0450.00460.05587.643-31.52217.132
50.00810.0468-0.06763.1137-0.39650.5667-0.006-0.01730.0020.33140.0278-0.18480.03020.1456-0.02180.05020.0147-0.04020.06260.01290.062822.518-11.916.886
60.1126-0.19290.00070.4552-0.11860.2307-0.02160.0147-0.0005-0.0024-0.03150.00530.03390.02450.05310.0184-0.0024-0.00370.05380.01410.02839.558-15.1089.436
71.1841-0.18260.16190.0298-0.03840.86920.0213-0.0182-0.01910.0048-0.0020.0008-0.0581-0.0437-0.01930.045-0.0118-0.01210.0430.00680.0166-2.42-5.18319.783
81.21570.1426-0.18690.10710.0880.20890.05270.03750.02040.008-0.019-0.0073-0.02510.0018-0.03380.0318-0.0194-0.00940.05160.01140.03697.195-4.08213.803
90.4241-0.2343-0.11630.2211-0.30621.532-0.0288-0.1040.12480.05230.0611-0.068-0.14330.0327-0.03230.057-0.0234-0.01960.0499-0.0220.039911.3994.17422.643
100.7318-0.0755-0.14770.0937-0.25410.8760.07450.08450.03340.0126-0.03260.0063-0.08170.05-0.0420.0359-0.0055-0.00710.03960.02510.02749.898-0.1474.165
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A159 - 192
2X-RAY DIFFRACTION2A193 - 209
3X-RAY DIFFRACTION3A223 - 243
4X-RAY DIFFRACTION4A244 - 269
5X-RAY DIFFRACTION5A270 - 284
6X-RAY DIFFRACTION6A285 - 338
7X-RAY DIFFRACTION7A339 - 363
8X-RAY DIFFRACTION8A364 - 389
9X-RAY DIFFRACTION9A390 - 413
10X-RAY DIFFRACTION10A414 - 449

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