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- PDB-5u6i: Discovery of MLi-2, an Orally Available and Selective LRRK2 Inhib... -

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Basic information

Entry
Database: PDB / ID: 5u6i
TitleDiscovery of MLi-2, an Orally Available and Selective LRRK2 Inhibitor that Reduces Brain Kinase Activity
ComponentsMitogen-activated protein kinase 1
KeywordsTRANSFERASE/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
Mitogen-activated protein (MAP) kinase, ERK1/2 / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / 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 ...Mitogen-activated protein (MAP) kinase, ERK1/2 / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / 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-81Y / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.69 Å
AuthorsScott, 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.
CitationJournal: 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
DepositionDec 8, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 15, 2017Provider: repository / Type: Initial release
Revision 1.1Apr 26, 2017Group: Data collection / Database references
Revision 1.2Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / software
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Mitogen-activated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,0846
Polymers42,3621
Non-polymers7235
Water4,540252
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area770 Å2
ΔGint-56 kcal/mol
Surface area16000 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.178, 91.416, 62.541
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein Mitogen-activated protein kinase 1 / MAPK 1 / ERT1 / Extracellular signal-regulated kinase 2 / ERK-2 / MAP kinase isoform p42 / p42-MAPK ...MAPK 1 / ERT1 / Extracellular signal-regulated kinase 2 / ERK-2 / MAP kinase isoform p42 / p42-MAPK / Mitogen-activated protein kinase 2 / MAPK 2


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
#2: Chemical ChemComp-81Y / 3-[2-(morpholin-4-yl)pyridin-4-yl]-5-[(propan-2-yl)oxy]-1H-indazole / MLi-2


Mass: 338.404 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H22N4O2
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 252 / 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: 2.55 Å3/Da / Density % sol: 51.75 %
Crystal growTemperature: 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

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 10, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 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 shellResolution: 1.695→1.701 Å / Redundancy: 6.7 % / Rmerge(I) obs: 0.625 / % possible all: 100

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Processing

Software
NameVersionClassification
XDSVERSION December 6 2010data reduction
autoPROCdata scaling
BUSTER2.11.7refinement
MOLREPphasing
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1ERK

1erk
PDB Unreleased entry


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
RfactorNum. reflection% reflectionSelection details
Rfree0.186 2270 5.01 %RANDOM
Rwork0.168 ---
obs0.169 45301 99.1 %-
Displacement parametersBiso mean: 33.61 Å2
Baniso -1Baniso -2Baniso -3
1--1.8882 Å20 Å20 Å2
2--1.0502 Å20 Å2
3---0.838 Å2
Refine analyzeLuzzati coordinate error obs: 0.19 Å
Refinement stepCycle: LAST / Resolution: 1.69→17.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2768 0 45 252 3065
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.015699HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.9810305HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1260SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes74HARMONIC2
X-RAY DIFFRACTIONt_gen_planes840HARMONIC5
X-RAY DIFFRACTIONt_it5699HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.49
X-RAY DIFFRACTIONt_other_torsion13.88
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion368SEMIHARMONIC5
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_contact6345SEMIHARMONIC4
LS refinement shellResolution: 1.69→1.73 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.232 131 4.45 %
Rwork0.183 2813 -
all0.186 2944 -
obs--88.27 %
Refinement TLS params.Method: refined / Origin x: 52.3791 Å / Origin y: 19.4135 Å / Origin z: 19.2162 Å
111213212223313233
T-0.0533 Å2-0.0006 Å2-0.0045 Å2--0.0624 Å20.0146 Å2---0.0598 Å2
L0.7812 °2-0.3067 °2-0.3906 °2-0.8227 °20.1152 °2--0.9429 °2
S0.0063 Å °0.0852 Å °-0.0518 Å °-0.0633 Å °-0.0351 Å °0.0857 Å °-0.0114 Å °-0.0435 Å °0.0288 Å °
Refinement TLS groupSelection details: { A|* }

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