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Yorodumi- PDB-5u6i: Discovery of MLi-2, an Orally Available and Selective LRRK2 Inhib... -
+Open data
-Basic information
Entry | Database: PDB / ID: 5u6i | ||||||
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Title | Discovery of MLi-2, an Orally Available and Selective LRRK2 Inhibitor that Reduces Brain Kinase Activity | ||||||
Components | Mitogen-activated protein kinase 1 | ||||||
Keywords | TRANSFERASE/TRANSFERASE INHIBITOR / MLi-2 / LRRK2 / kinase inhibitor / kinase selectivity / Parkinson's disease / TRANSFERASE / SERINE/ THREONINE-PROTEIN KINASE / MAP KINASE / TRANSFERASE-TRANSFERASE INHIBITOR COMPLEX | ||||||
Function / homology | Function and homology information phospho-PLA2 pathway / RAF-independent MAPK1/3 activation / MAPK1 (ERK2) activation / Signaling by NODAL / Frs2-mediated activation / ERK/MAPK targets / ERKs are inactivated / Activation of the AP-1 family of transcription factors / RHO GTPases Activate WASPs and WAVEs / IFNG signaling activates MAPKs ...phospho-PLA2 pathway / RAF-independent MAPK1/3 activation / MAPK1 (ERK2) activation / Signaling by NODAL / Frs2-mediated activation / ERK/MAPK targets / ERKs are inactivated / Activation of the AP-1 family of transcription factors / RHO GTPases Activate WASPs and WAVEs / IFNG signaling activates MAPKs / Negative feedback regulation of MAPK pathway / Gastrin-CREB signalling pathway via PKC and MAPK / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / Golgi Cisternae Pericentriolar Stack Reorganization / Regulation of actin dynamics for phagocytic cup formation / Estrogen-stimulated signaling through PRKCZ / Growth hormone receptor signaling / Spry regulation of FGF signaling / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / Oxidative Stress Induced Senescence / Senescence-Associated Secretory Phenotype (SASP) / Oncogene Induced Senescence / Signaling by Activin / Downregulation of SMAD2/3:SMAD4 transcriptional activity / Signal attenuation / NCAM signaling for neurite out-growth / Negative regulation of FGFR1 signaling / Negative regulation of FGFR3 signaling / Negative regulation of FGFR4 signaling / Regulation of the apoptosome activity / Signal transduction by L1 / Negative regulation of FGFR2 signaling / RHO GTPases Activate NADPH Oxidases / Negative regulation of MAPK pathway / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Interferon gamma signaling / FCERI mediated MAPK activation / Regulation of HSF1-mediated heat shock response / MAP2K and MAPK activation / Recycling pathway of L1 / neural crest cell development / diadenosine tetraphosphate biosynthetic process / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / cytosine metabolic process / response to epidermal growth factor / mitogen-activated protein kinase kinase kinase binding / positive regulation of macrophage proliferation / outer ear morphogenesis / Thrombin signalling through proteinase activated receptors (PARs) / regulation of cellular pH / RAF/MAP kinase cascade / regulation of Golgi inheritance / ERBB signaling pathway / labyrinthine layer blood vessel development / mammary gland epithelial cell proliferation / trachea formation / Neutrophil degranulation / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / : / positive regulation of macrophage chemotaxis / lung morphogenesis / ERBB2-ERBB3 signaling pathway / response to exogenous dsRNA / regulation of cytoskeleton organization / face development / progesterone receptor signaling pathway / androgen receptor signaling pathway / pseudopodium / Bergmann glial cell differentiation / negative regulation of cell differentiation / positive regulation of telomere capping / thyroid gland development / decidualization / steroid hormone receptor signaling pathway / MAP kinase activity / regulation of ossification / phosphatase binding / mitogen-activated protein kinase / Schwann cell development / stress-activated MAPK cascade / positive regulation of cardiac muscle cell proliferation / lipopolysaccharide-mediated signaling pathway / sensory perception of pain / positive regulation of telomere maintenance via telomerase / cellular response to cadmium ion / ERK1 and ERK2 cascade / myelination / cellular response to amino acid starvation / dendrite cytoplasm / phosphotyrosine residue binding / RNA polymerase II CTD heptapeptide repeat kinase activity / insulin-like growth factor receptor signaling pathway / thymus development / positive regulation of peptidyl-threonine phosphorylation / caveola / positive regulation of translation / long-term synaptic potentiation / animal organ morphogenesis Similarity search - Function | ||||||
Biological species | Rattus norvegicus (Norway rat) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.69 Å | ||||||
Authors | Scott, J.D. / DeMong, D.E. / Fell, M.J. / Mirescu, C. / Basu, K. / Greshock, T.J. / Morrow, J.A. / Xiao, L. / Hruza, A. / Harris, J. ...Scott, J.D. / DeMong, D.E. / Fell, M.J. / Mirescu, C. / Basu, K. / Greshock, T.J. / Morrow, J.A. / Xiao, L. / Hruza, A. / Harris, J. / Tiscia, H.E. / Chang, R.K. / Embrey, M.W. / McCauley, J.A. / Li, W. / Lin, S. / Liu, H. / Dai, X. / Baptista, M. / Agnihotri, G. / Columbus, J. / Mei, H. / Poirier, M. / Zhou, X. / Lin, Y. / Yin, Z. / Sanders, J.M. / Drolet, R.E. / Kern, J.T. / Kennedy, M.E. / Parker, E.M. / Stamford, A.W. / Nargund, R. / Miller, M.W. | ||||||
Citation | Journal: J. Med. Chem. / Year: 2017 Title: Discovery of a 3-(4-Pyrimidinyl) Indazole (MLi-2), an Orally Available and Selective Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitor that Reduces Brain Kinase Activity. Authors: Scott, J.D. / DeMong, D.E. / Greshock, T.J. / Basu, K. / Dai, X. / Harris, J. / Hruza, A. / Li, S.W. / Lin, S.I. / Liu, H. / Macala, M.K. / Hu, Z. / Mei, H. / Zhang, H. / Walsh, P. / ...Authors: Scott, J.D. / DeMong, D.E. / Greshock, T.J. / Basu, K. / Dai, X. / Harris, J. / Hruza, A. / Li, S.W. / Lin, S.I. / Liu, H. / Macala, M.K. / Hu, Z. / Mei, H. / Zhang, H. / Walsh, P. / Poirier, M. / Shi, Z.C. / Xiao, L. / Agnihotri, G. / Baptista, M.A. / Columbus, J. / Fell, M.J. / Hyde, L.A. / Kuvelkar, R. / Lin, Y. / Mirescu, C. / Morrow, J.A. / Yin, Z. / Zhang, X. / Zhou, X. / Chang, R.K. / Embrey, M.W. / Sanders, J.M. / Tiscia, H.E. / Drolet, R.E. / Kern, J.T. / Sur, S.M. / Renger, J.J. / Bilodeau, M.T. / Kennedy, M.E. / Parker, E.M. / Stamford, A.W. / Nargund, R. / McCauley, J.A. / Miller, M.W. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 5u6i.cif.gz | 291.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb5u6i.ent.gz | 237.2 KB | Display | PDB format |
PDBx/mmJSON format | 5u6i.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 5u6i_validation.pdf.gz | 731 KB | Display | wwPDB validaton report |
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Full document | 5u6i_full_validation.pdf.gz | 733.6 KB | Display | |
Data in XML | 5u6i_validation.xml.gz | 16.5 KB | Display | |
Data in CIF | 5u6i_validation.cif.gz | 24.3 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/u6/5u6i ftp://data.pdbj.org/pub/pdb/validation_reports/u6/5u6i | HTTPS FTP |
-Related structure data
Related structure data | 1erk S: Starting model for refinement |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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-Components
#1: Protein | Mass: 42361.703 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Mapk1, Erk2, Mapk, Prkm1 / Production host: Escherichia coli (E. coli) References: UniProt: P63086, mitogen-activated protein kinase | ||
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#2: Chemical | ChemComp-81Y / | ||
#3: Chemical | ChemComp-SO4 / #4: Water | ChemComp-HOH / | |
-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.55 Å3/Da / Density % sol: 51.75 % |
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Crystal grow | Temperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.4 Details: 0.1M MES, PH 6.4, 2.0M AMMONIUM SULFATE, 5% PEG 400, 0.5% DMSO, 1% GLYEROL, 0.0005M OLOMOUCINE, 18 DAY SOAK WITH NEW COMPOUND AT 500 MICROMOLAR CONCENTRATION |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å |
Detector | Type: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 10, 2011 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1 Å / Relative weight: 1 |
Reflection | Resolution: 1.69→17.04 Å / Num. obs: 45409 / % possible obs: 100 % / Redundancy: 6.4 % / Biso Wilson estimate: 28.4 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 17.2 |
Reflection shell | Resolution: 1.695→1.701 Å / Redundancy: 6.7 % / Rmerge(I) obs: 0.625 / % possible all: 100 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 1ERK 1erk Resolution: 1.69→17.04 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.957 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.107 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.09 / SU Rfree Blow DPI: 0.084 / SU Rfree Cruickshank DPI: 0.082
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Displacement parameters | Biso mean: 33.61 Å2
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Refine analyze | Luzzati coordinate error obs: 0.19 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 1.69→17.04 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 1.69→1.73 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
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Refinement TLS params. | Method: refined / Origin x: 52.3791 Å / Origin y: 19.4135 Å / Origin z: 19.2162 Å
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Refinement TLS group | Selection details: { A|* } |