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- PDB-5vt1: Crystal Structure of the Human CAMKK2B bound to a thiadiazinone b... -

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Basic information

Entry
Database: PDB / ID: 5vt1
TitleCrystal Structure of the Human CAMKK2B bound to a thiadiazinone benzamide inhibitor
ComponentsCalcium/calmodulin-dependent protein kinase kinase 2
KeywordsTransferase/Transferase Inhibitor / transferase / protein kinase domain / Structural Genomics / Structural Genomics Consortium / SGC / 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 / calmodulin-dependent protein kinase activity / regulation of protein kinase activity / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / 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 / calmodulin-dependent protein kinase activity / regulation of protein kinase activity / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / 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-9JS / Calcium/calmodulin-dependent protein kinase kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsCounago, R.M. / Asquith, C.R.M. / Arruda, P. / Edwards, A.M. / Gileadi, O. / Kalogirou, A.S. / Koutentis, P.A. / Structural Genomics Consortium (SGC)
Funding support Brazil, 1items
OrganizationGrant numberCountry
Sao Paulo Research Foundation (FAPESP)13/50724-5 Brazil
CitationJournal: Molecules / Year: 2018
Title: 1,2,6-Thiadiazinones as Novel Narrow Spectrum Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) Inhibitors.
Authors: Asquith, C.R.M. / Godoi, P.H. / Counago, R.M. / Laitinen, T. / Scott, J.W. / Langendorf, C.G. / Oakhill, J.S. / Drewry, D.H. / Zuercher, W.J. / Koutentis, P.A. / Willson, T.M. / Kalogirou, A.S.
History
DepositionMay 15, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 24, 2017Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2017Group: Structure summary / Category: audit_author / struct / Item: _struct.title
Revision 1.2May 30, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.3Jun 6, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.pdbx_database_id_PubMed ..._citation.journal_volume / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.4Apr 17, 2019Group: Author supporting evidence / Data collection / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.5Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.6Oct 4, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_symmetry

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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)33,5213
Polymers33,1271
Non-polymers3942
Water4,432246
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)100.454, 100.454, 69.674
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number169
Space group name H-MP61

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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: UNP 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) / Strain (production host): BL21(DE3) / Variant (production host): R3
References: UniProt: Q96RR4, Ca2+/calmodulin-dependent protein kinase
#2: Chemical ChemComp-9JS / 4-({5-[(3-hydroxy-4-methylphenyl)amino]-4-oxo-4H-1,2,6-thiadiazin-3-yl}amino)benzamide


Mass: 369.398 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H15N5O3S
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 246 / 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: 3.06 Å3/Da / Density % sol: 59.85 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 24% PEG 8000, 0.1M magnesium acetate, 0.1M CHC buffer (citric acid, ches, hepes).

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Jan 25, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 1.9→19.96 Å / Num. obs: 31197 / % possible obs: 98.7 % / Redundancy: 5.1 % / Biso Wilson estimate: 26.27 Å2 / CC1/2: 0.988 / Rmerge(I) obs: 0.14 / Rpim(I) all: 0.066 / Net I/σ(I): 7.3
Reflection shellResolution: 1.9→1.94 Å / Redundancy: 5.2 % / Rmerge(I) obs: 0.575 / Num. unique obs: 2111 / CC1/2: 0.836 / Rpim(I) all: 0.275 / % possible all: 99.7

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Processing

Software
NameVersionClassification
BUSTER2.10.3refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2zv2

2zv2


Resolution: 1.9→19.96 Å / Cor.coef. Fo:Fc: 0.932 / Cor.coef. Fo:Fc free: 0.924 / SU R Cruickshank DPI: 0.129 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.105 / SU Rfree Blow DPI: 0.099 / SU Rfree Cruickshank DPI: 0.097
RfactorNum. reflection% reflectionSelection details
Rfree0.185 1446 4.64 %RANDOM
Rwork0.161 ---
obs0.162 31193 98.7 %-
Displacement parametersBiso mean: 33.95 Å2
Baniso -1Baniso -2Baniso -3
1-7.2067 Å20 Å20 Å2
2--7.2067 Å20 Å2
3----14.4134 Å2
Refinement stepCycle: 1 / Resolution: 1.9→19.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2096 0 27 246 2369
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014252HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.037712HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1194SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes57HARMONIC2
X-RAY DIFFRACTIONt_gen_planes606HARMONIC5
X-RAY DIFFRACTIONt_it4252HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.64
X-RAY DIFFRACTIONt_other_torsion2.89
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion278SEMIHARMONIC5
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_contact4639SEMIHARMONIC4
LS refinement shellResolution: 1.9→1.96 Å / Total num. of bins used: 16
RfactorNum. reflection% reflection
Rfree0.2253 153 5.31 %
Rwork0.17 2726 -
all0.1728 2879 -
obs--99.58 %
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)
12.13130.35040.01844.8316-2.04121.81280.0565-0.08050.057-0.01740.35340.92490.1323-0.4135-0.4099-0.0975-0.0140.0266-0.0640.12580.029422.37444.890333.2445
22.95991.9435-0.60213.7988-0.68794.97110.0208-0.1717-0.26440.3347-0.04250.0099-0.005-0.01390.02170.0516-0.0105-0.01420.00640.0666-0.007237.013241.283439.8498
31.27550.31480.13611.7499-0.37330.23060.0396-0.1085-0.0740.21030.01320.0565-0.0144-0.0369-0.0528-0.01060.0102-0.0197-0.02660.0033-0.078642.056152.395331.9275
42.27770.15610.46542.79720.77541.5834-0.0360.2624-0.0159-0.2292-0.0268-0.0617-0.07480.08510.0628-0.05210.0069-0.0154-0.0254-0.0065-0.089954.624556.526121.634
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{A|160 - 205}
2X-RAY DIFFRACTION2{A|227 - 242}
3X-RAY DIFFRACTION3{A|243 - 385}
4X-RAY DIFFRACTION4{A|386 - 448}

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