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- PDB-5vlo: The structure of human CamKII with bound inhibitor -

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Basic information

Entry
Database: PDB / ID: 5vlo
TitleThe structure of human CamKII with bound inhibitor
ComponentsCalcium/calmodulin-dependent protein kinase type II subunit delta
KeywordsTRANSFERASE / Kinase / CamKII / inhibitor
Function / homology
Function and homology information


regulation of relaxation of cardiac muscle / regulation of cellular localization / negative regulation of sodium ion transmembrane transport / calcium- and calmodulin-dependent protein kinase complex / regulation of cardiac muscle cell action potential involved in regulation of contraction / regulation of cell communication by electrical coupling / negative regulation of sodium ion transmembrane transporter activity / Ca2+/calmodulin-dependent protein kinase / regulation of the force of heart contraction / Trafficking of AMPA receptors ...regulation of relaxation of cardiac muscle / regulation of cellular localization / negative regulation of sodium ion transmembrane transport / calcium- and calmodulin-dependent protein kinase complex / regulation of cardiac muscle cell action potential involved in regulation of contraction / regulation of cell communication by electrical coupling / negative regulation of sodium ion transmembrane transporter activity / Ca2+/calmodulin-dependent protein kinase / regulation of the force of heart contraction / Trafficking of AMPA receptors / cardiac muscle cell contraction / endoplasmic reticulum calcium ion homeostasis / Assembly and cell surface presentation of NMDA receptors / sodium channel inhibitor activity / calmodulin-dependent protein kinase activity / regulation of heart contraction / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / relaxation of cardiac muscle / CaMK IV-mediated phosphorylation of CREB / regulation of cardiac muscle cell action potential / regulation of membrane depolarization / Negative regulation of NMDA receptor-mediated neuronal transmission / positive regulation of cardiac muscle hypertrophy / positive regulation of cardiac muscle cell apoptotic process / regulation of cell communication by electrical coupling involved in cardiac conduction / Unblocking of NMDA receptors, glutamate binding and activation / regulation of heart rate by cardiac conduction / Phase 0 - rapid depolarisation / Long-term potentiation / Ion transport by P-type ATPases / Regulation of MECP2 expression and activity / HSF1-dependent transactivation / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / titin binding / regulation of ryanodine-sensitive calcium-release channel activity / Ion homeostasis / sarcoplasmic reticulum membrane / cellular response to calcium ion / Ras activation upon Ca2+ influx through NMDA receptor / regulation of cell growth / peptidyl-threonine phosphorylation / RAF activation / sarcolemma / endocytic vesicle membrane / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / Interferon gamma signaling / Signaling by BRAF and RAF1 fusions / RAF/MAP kinase cascade / peptidyl-serine phosphorylation / transmembrane transporter binding / protein autophosphorylation / calmodulin binding / neuron projection / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / regulation of transcription by RNA polymerase II / protein homodimerization activity / nucleoplasm / ATP binding / membrane / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Calcium/calmodulin-dependent protein kinase II, association-domain / Calcium/calmodulin dependent protein kinase II association domain / NTF2-like domain superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain ...Calcium/calmodulin-dependent protein kinase II, association-domain / Calcium/calmodulin dependent protein kinase II association domain / NTF2-like domain superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-9EJ / 2,3-DIHYDROXY-1,4-DITHIOBUTANE / Calcium/calmodulin-dependent protein kinase type II subunit delta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.05 Å
AuthorsSomoza, J.R. / Villasenor, A.G.
CitationJournal: To Be Published
Title: Inhibitors of CamKII
Authors: Somoza, T.J. / Villasenor, A.G.
History
DepositionApr 25, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 23, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 27, 2017Group: Data collection / Category: diffrn_detector / Item: _diffrn_detector.detector
Revision 1.2Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Calcium/calmodulin-dependent protein kinase type II subunit delta
B: Calcium/calmodulin-dependent protein kinase type II subunit delta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,3216
Polymers68,9192
Non-polymers1,4024
Water6,287349
1
A: Calcium/calmodulin-dependent protein kinase type II subunit delta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1613
Polymers34,4601
Non-polymers7012
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Calcium/calmodulin-dependent protein kinase type II subunit delta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1613
Polymers34,4601
Non-polymers7012
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)54.473, 67.546, 85.450
Angle α, β, γ (deg.)90.000, 94.111, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Protein Calcium/calmodulin-dependent protein kinase type II subunit delta / CaMK-II subunit delta


Mass: 34459.574 Da / Num. of mol.: 2 / Fragment: UNP residues 3-301
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CAMK2D, CAMKD / Production host: Escherichia coli (E. coli)
References: UniProt: Q13557, Ca2+/calmodulin-dependent protein kinase
#2: Chemical ChemComp-9EJ / N-[(2S)-2-(diethylamino)propyl]-2-[(2S)-2-(methylcarbamoyl)azetidin-1-yl]-6-[5-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl]pyridine-4-carboxamide


Mass: 546.687 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H34N8O2S
#3: Chemical ChemComp-DTT / 2,3-DIHYDROXY-1,4-DITHIOBUTANE / 1,4-DITHIOTHREITOL / Dithiothreitol


Mass: 154.251 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O2S2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 349 / 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: 2.35 Å3/Da / Density % sol: 47.64 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: CamKII S3-K301, in 20mM imidazole pH 8.5, 0.3M sodium chloride, 5mM TCEP, was concentrated to 36 mg/ml and flash frozen in liquid nitrogen for long term storage at -80 C in 10 uL aliquots. ...Details: CamKII S3-K301, in 20mM imidazole pH 8.5, 0.3M sodium chloride, 5mM TCEP, was concentrated to 36 mg/ml and flash frozen in liquid nitrogen for long term storage at -80 C in 10 uL aliquots. The protein was thawed and diluted down to 12 mg/mL in the same buffer just prior to crystallization experiments. Sitting drop vapor diffusion droplets were assembled with 250 nL of 12 mg/mL CamKII, 0.6 mM inhibitor and 250 nL of reservoir solution 24% peg 3350, 0.2 M ammonium tartrate, 0.1 M arginine. Flat crystal plates (typically 0.03 mm x 0.2 mm x 0.4 mm in size) grew in 4-7 days at 20 C. A crystal seed suspension was prepared with ten crushed crystals combined into 100 uL of reservoir solution and stored at -80 C. A thirty fold seed dilution was prepared in the same solution for addition to protein droplets in a 1 to 1 volume ratio to enhance crystallization of difficult to crystallize inhibitors.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Feb 25, 2016
RadiationMonochromator: Double-crystal, Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.05→50 Å / Num. obs: 38959 / % possible obs: 98.5 % / Redundancy: 13 % / Biso Wilson estimate: 34.660655594 Å2 / CC1/2: 0.998 / Net I/σ(I): 12.7
Reflection shellResolution: 2.05→2.17 Å / Redundancy: 12.7 % / Mean I/σ(I) obs: 1.63 / Num. unique obs: 5733 / CC1/2: 0.742 / % possible all: 91

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
EPMRphasing
PHENIX1.10.1_2155refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.05→47.38 Å / SU ML: 0.220732142541 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 25.0433043868
RfactorNum. reflection% reflection
Rfree0.2261 1453 1.91483354296 %
Rwork0.1828 --
obs0.1837 38959 99.9692078725 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 41.0908881426 Å2
Refinement stepCycle: LAST / Resolution: 2.05→47.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4694 0 94 349 5137
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.002736100930554907
X-RAY DIFFRACTIONf_angle_d0.5179261312396639
X-RAY DIFFRACTIONf_chiral_restr0.0412273122249709
X-RAY DIFFRACTIONf_plane_restr0.00435645601269848
X-RAY DIFFRACTIONf_dihedral_angle_d18.79078262262921
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.05-2.20830.31460.26597567X-RAY DIFFRACTION99.9611197512
2.2083-2.43050.307831520.22517613X-RAY DIFFRACTION99.9613800206
2.4305-2.78220.26721520.20487608X-RAY DIFFRACTION100
2.7822-3.50510.21361500.18757654X-RAY DIFFRACTION99.9743786831
3.5051-47.39340.19121460.15147771X-RAY DIFFRACTION99.9621212121

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