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Yorodumi- PDB-2kuh: Halothane binds to druggable sites in calcium-calmodulin: Solutio... -
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-Basic information
Entry | Database: PDB / ID: 2kuh | ||||||
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Title | Halothane binds to druggable sites in calcium-calmodulin: Solution structure of halothane-CaM C-terminal domain | ||||||
Components | Calmodulin | ||||||
Keywords | METAL BINDING PROTEIN / CALMODULIN / CALCIUM BINDING / VOLATILE ANESTHETIC / HALOTHANE / Cytoskeleton / Isopeptide bond / Methylation / Phosphoprotein | ||||||
Function / homology | Function and homology information : / establishment of protein localization to mitochondrial membrane / type 3 metabotropic glutamate receptor binding / CaM pathway / Cam-PDE 1 activation / Sodium/Calcium exchangers / Calmodulin induced events / regulation of synaptic vesicle endocytosis / Reduction of cytosolic Ca++ levels / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde ...: / establishment of protein localization to mitochondrial membrane / type 3 metabotropic glutamate receptor binding / CaM pathway / Cam-PDE 1 activation / Sodium/Calcium exchangers / Calmodulin induced events / regulation of synaptic vesicle endocytosis / Reduction of cytosolic Ca++ levels / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / Activation of Ca-permeable Kainate Receptor / Loss of phosphorylation of MECP2 at T308 / CREB1 phosphorylation through the activation of Adenylate Cyclase / PKA activation / negative regulation of high voltage-gated calcium channel activity / CaMK IV-mediated phosphorylation of CREB / Glycogen breakdown (glycogenolysis) / positive regulation of cyclic-nucleotide phosphodiesterase activity / regulation of synaptic vesicle exocytosis / organelle localization by membrane tethering / negative regulation of calcium ion export across plasma membrane / CLEC7A (Dectin-1) induces NFAT activation / mitochondrion-endoplasmic reticulum membrane tethering / autophagosome membrane docking / regulation of cardiac muscle cell action potential / Activation of RAC1 downstream of NMDARs / response to corticosterone / positive regulation of DNA binding / positive regulation of ryanodine-sensitive calcium-release channel activity / nitric-oxide synthase binding / regulation of cell communication by electrical coupling involved in cardiac conduction / Negative regulation of NMDA receptor-mediated neuronal transmission / negative regulation of peptidyl-threonine phosphorylation / Synthesis of IP3 and IP4 in the cytosol / Unblocking of NMDA receptors, glutamate binding and activation / Phase 0 - rapid depolarisation / negative regulation of ryanodine-sensitive calcium-release channel activity / protein phosphatase activator activity / RHO GTPases activate PAKs / : / Ion transport by P-type ATPases / Long-term potentiation / Uptake and function of anthrax toxins / Regulation of MECP2 expression and activity / Calcineurin activates NFAT / adenylate cyclase binding / catalytic complex / DARPP-32 events / detection of calcium ion / regulation of cardiac muscle contraction / regulation of ryanodine-sensitive calcium-release channel activity / Smooth Muscle Contraction / cellular response to interferon-beta / RHO GTPases activate IQGAPs / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / calcium channel inhibitor activity / Protein methylation / phosphatidylinositol 3-kinase binding / eNOS activation / enzyme regulator activity / activation of adenylate cyclase activity / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / Activation of AMPK downstream of NMDARs / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / : / Ion homeostasis / titin binding / regulation of calcium-mediated signaling / positive regulation of protein autophosphorylation / voltage-gated potassium channel complex / sperm midpiece / calcium channel complex / response to amphetamine / substantia nigra development / adenylate cyclase activator activity / Ras activation upon Ca2+ influx through NMDA receptor / nitric-oxide synthase regulator activity / regulation of heart rate / sarcomere / FCERI mediated Ca+2 mobilization / protein serine/threonine kinase activator activity / FCGR3A-mediated IL10 synthesis / VEGFR2 mediated vascular permeability / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / VEGFR2 mediated cell proliferation / regulation of cytokinesis / positive regulation of peptidyl-threonine phosphorylation / positive regulation of nitric-oxide synthase activity / Translocation of SLC2A4 (GLUT4) to the plasma membrane / spindle microtubule / mitochondrial membrane / RAF activation / positive regulation of receptor signaling pathway via JAK-STAT / Transcriptional activation of mitochondrial biogenesis / positive regulation of protein serine/threonine kinase activity / Stimuli-sensing channels / cellular response to type II interferon / spindle pole / synaptic vesicle membrane / response to calcium ion Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | SOLUTION NMR / simulated annealing, CHARMm22 energy minimization | ||||||
Model details | closest to the average, model 1 | ||||||
Authors | Juranic, N. / Macura, S. / Simeonov, M.V. / Jones, K.A. / Penheiter, A.R. / Hock, T.J. / Streiff, J.H. | ||||||
Citation | Journal: J. Serb. Chem. Soc. / Year: 2013 Title: Halothane binds to druggable sites in the [Ca2+]4-calmodulin (CaM) complex, but does not inhibit [Ca2+]4-CaM activation of kinase. Authors: Juranic, N.O. / Jones, K.A. / Penheiter, A.R. / Hock, T.J. / Streiff, J.H. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 2kuh.cif.gz | 119.6 KB | Display | PDBx/mmCIF format |
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PDB format | pdb2kuh.ent.gz | 96.6 KB | Display | PDB format |
PDBx/mmJSON format | 2kuh.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/ku/2kuh ftp://data.pdbj.org/pub/pdb/validation_reports/ku/2kuh | HTTPS FTP |
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-Related structure data
-Links
-Assembly
Deposited unit |
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1 |
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NMR ensembles |
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-Components
#1: Protein | Mass: 7737.468 Da / Num. of mol.: 1 / Fragment: C-TERMINAL DOMAIN EF-hands 3 and 4 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) Gene: CALM1, CALM, CAM, CAM1, CALM2, CAM2, CAMB, CALM3, CALML2, CAM3, CAMC, CAMIII Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3)-pLysS / References: UniProt: P62158, UniProt: P0DP23*PLUS | ||
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#2: Chemical | #3: Chemical | ChemComp-HLT / | |
-Experimental details
-Experiment
Experiment | Method: SOLUTION NMR Details: The mechanism(s) of volatile anesthetic effects are poorly understood. We examined whether VA binding to druggable sites in calmodulin would effect [Ca2+]4-CaM dependent activity of enzymes. ...Details: The mechanism(s) of volatile anesthetic effects are poorly understood. We examined whether VA binding to druggable sites in calmodulin would effect [Ca2+]4-CaM dependent activity of enzymes. We used high resolution NMR spectroscopy to determine the structure of the halothane [Ca2+]4-CaM complex, determining that the halothane molecules bind in the druggable sites. We used fluorescence assays to determine that VA mediate [Ca2+]4-CaM activation of smMLCK, but not the kd of [Ca2+]4-CaM binding to skMLCK. These results suggest that VA do not mediate [Ca2+]4-CaM dependent MLCK activity via direct interactions with druggable sites on [Ca2+]4-CaM. | ||||||||||||||||||||||||||||||||||||||||||||||||
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NMR experiment |
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-Sample preparation
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Sample |
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Sample conditions | Ionic strength: 0.1 / pH: 7.2 / Pressure: ambient / Temperature: 298 K |
-NMR measurement
NMR spectrometer |
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-Processing
NMR software |
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Refinement | Method: simulated annealing, CHARMm22 energy minimization / Software ordinal: 1 Details: XPLOR, 100 steps steepest descend - final refinement | ||||||||||||
NMR constraints | NOE constraints total: 808 / NOE intraresidue total count: 337 / NOE long range total count: 137 / NOE medium range total count: 137 / NOE sequential total count: 188 / Hydrogen bond constraints total count: 46 / Protein chi angle constraints total count: 65 / Protein other angle constraints total count: 65 / Protein phi angle constraints total count: 65 / Protein psi angle constraints total count: 65 | ||||||||||||
NMR representative | Selection criteria: closest to the average | ||||||||||||
NMR ensemble | Conformer selection criteria: structures with the lowest energy Conformers calculated total number: 50 / Conformers submitted total number: 5 |