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- PDB-2w1i: Structure determination of Aurora Kinase in complex with inhibitor -

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Basic information

Entry
Database: PDB / ID: 2w1i
TitleStructure determination of Aurora Kinase in complex with inhibitor
ComponentsJAK2
KeywordsTRANSFERASE / CHROMOSOMAL REARRANGEMENT / NUCLEOTIDE-BINDING / TYROSINE-PROTEIN KINASE / PROTO-ONCOGENE / PHOSPHOPROTEIN / DISEASE MUTATION / SH2 DOMAIN / ATP-BINDING / POLYMORPHISM / KINASE / CANCER / AURORA / MEMBRANE / INHIBITOR
Function / homology
Function and homology information


interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid signaling pathway / histone H3Y41 kinase activity / : / positive regulation of growth factor dependent skeletal muscle satellite cell proliferation / symbiont-induced defense-related programmed cell death / mammary gland epithelium development / regulation of postsynapse to nucleus signaling pathway / positive regulation of growth hormone receptor signaling pathway / granulocyte macrophage colony-stimulating factor receptor complex ...interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid signaling pathway / histone H3Y41 kinase activity / : / positive regulation of growth factor dependent skeletal muscle satellite cell proliferation / symbiont-induced defense-related programmed cell death / mammary gland epithelium development / regulation of postsynapse to nucleus signaling pathway / positive regulation of growth hormone receptor signaling pathway / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway / Signaling by Erythropoietin / collagen-activated signaling pathway / interleukin-23-mediated signaling pathway / interleukin-12 receptor binding / Erythropoietin activates STAT5 / response to interleukin-12 / interleukin-5-mediated signaling pathway / Erythropoietin activates Phospholipase C gamma (PLCG) / positive regulation of leukocyte proliferation / post-embryonic hemopoiesis / erythropoietin-mediated signaling pathway / interleukin-12 receptor complex / activation of Janus kinase activity / tyrosine phosphorylation of STAT protein / interleukin-23 receptor complex / Interleukin-23 signaling / positive regulation of platelet aggregation / positive regulation of T-helper 17 type immune response / positive regulation of MHC class II biosynthetic process / interleukin-12-mediated signaling pathway / acetylcholine receptor binding / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / positive regulation of platelet activation / interleukin-3-mediated signaling pathway / cellular response to interleukin-3 / regulation of nitric oxide biosynthetic process / Signaling by Leptin / Interleukin-12 signaling / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-35 Signalling / positive regulation of signaling receptor activity / positive regulation of epithelial cell apoptotic process / positive regulation of natural killer cell proliferation / positive regulation of cell-substrate adhesion / regulation of receptor signaling pathway via JAK-STAT / growth hormone receptor binding / growth hormone receptor signaling pathway / axon regeneration / response to hydroperoxide / negative regulation of cardiac muscle cell apoptotic process / intrinsic apoptotic signaling pathway in response to oxidative stress / extrinsic component of plasma membrane / peptide hormone receptor binding / Interleukin-20 family signaling / IFNG signaling activates MAPKs / Interleukin-6 signaling / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / negative regulation of cell-cell adhesion / interleukin-6-mediated signaling pathway / enzyme-linked receptor protein signaling pathway / Prolactin receptor signaling / MAPK3 (ERK1) activation / response to amine / negative regulation of DNA binding / extrinsic component of cytoplasmic side of plasma membrane / mesoderm development / positive regulation of nitric-oxide synthase biosynthetic process / positive regulation of interleukin-17 production / MAPK1 (ERK2) activation / positive regulation of SMAD protein signal transduction / cell surface receptor signaling pathway via JAK-STAT / platelet-derived growth factor receptor signaling pathway / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / type II interferon-mediated signaling pathway / growth hormone receptor signaling pathway via JAK-STAT / Interleukin receptor SHC signaling / response to tumor necrosis factor / phosphatidylinositol 3-kinase binding / Regulation of IFNG signaling / Erythropoietin activates RAS / Signaling by CSF3 (G-CSF) / Growth hormone receptor signaling / positive regulation of T cell proliferation / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of vascular associated smooth muscle cell proliferation / tumor necrosis factor-mediated signaling pathway / extrinsic apoptotic signaling pathway / post-translational protein modification / actin filament polymerization / SH2 domain binding / cellular response to dexamethasone stimulus / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / erythrocyte differentiation / positive regulation of interleukin-1 beta production / endosome lumen / positive regulation of cell differentiation
Similarity search - Function
Tyrosine-protein kinase, non-receptor Jak2 / Janus kinase 2, pseudokinase domain / Janus kinase 2, catalytic domain / Tyrosine-protein kinase JAK2, SH2 domain / JAK2, FERM domain C-lobe / SH2 domain / Tyrosine-protein kinase, non-receptor Jak/Tyk2 / JAK, FERM F2 lobe domain / FERM F1 lobe ubiquitin-like domain / JAK1-3/TYK2, pleckstrin homology-like domain ...Tyrosine-protein kinase, non-receptor Jak2 / Janus kinase 2, pseudokinase domain / Janus kinase 2, catalytic domain / Tyrosine-protein kinase JAK2, SH2 domain / JAK2, FERM domain C-lobe / SH2 domain / Tyrosine-protein kinase, non-receptor Jak/Tyk2 / JAK, FERM F2 lobe domain / FERM F1 lobe ubiquitin-like domain / JAK1-3/TYK2, pleckstrin homology-like domain / : / Jak1 pleckstrin homology-like domain / FERM F2 acyl-CoA binding protein-like domain / FERM F1 ubiquitin-like domain / FERM central domain / FERM superfamily, second domain / FERM domain / FERM domain profile. / Band 4.1 domain / Band 4.1 homologues / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / SH2 domain superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / PH-like domain superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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-L0I / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / OTHER / Resolution: 2.6 Å
AuthorsHoward, S. / Berdini, V. / Boulstridge, J.A. / Carr, M.G. / Cross, D.M. / Curry, J. / Devine, L.A. / Early, T.R. / Fazal, L. / Gill, A.L. ...Howard, S. / Berdini, V. / Boulstridge, J.A. / Carr, M.G. / Cross, D.M. / Curry, J. / Devine, L.A. / Early, T.R. / Fazal, L. / Gill, A.L. / Heathcote, M. / Maman, S. / Matthews, J.E. / McMenamin, R.L. / Navarro, E.F. / O'Brien, M.A. / O'Reilly, M. / Rees, D.C. / Reule, M. / Tisi, D. / Williams, G. / Vinkovic, M. / Wyatt, P.G.
CitationJournal: J.Med.Chem. / Year: 2009
Title: Fragment-Based Discovery of the Pyrazol-4-Yl Urea (at9283), a Multitargeted Kinase Inhibitor with Potent Aurora Kinase Activity.
Authors: Howard, S. / Berdini, V. / Boulstridge, J.A. / Carr, M.G. / Cross, D.M. / Curry, J. / Devine, L.A. / Early, T.R. / Fazal, L. / Gill, A.L. / Heathcote, M. / Maman, S. / Matthews, J.E. / ...Authors: Howard, S. / Berdini, V. / Boulstridge, J.A. / Carr, M.G. / Cross, D.M. / Curry, J. / Devine, L.A. / Early, T.R. / Fazal, L. / Gill, A.L. / Heathcote, M. / Maman, S. / Matthews, J.E. / Mcmenamin, R.L. / Navarro, E.F. / O'Brien, M.A. / O'Reilly, M. / Rees, D.C. / Reule, M. / Tisi, D. / Williams, G. / Vinkovic, M. / Wyatt, P.G.
History
DepositionOct 17, 2008Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 27, 2009Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 23, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_entry_details / pdbx_modification_feature / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_conn.pdbx_leaving_atom_flag

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: JAK2
B: JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,5623
Polymers77,1792
Non-polymers3821
Water2,360131
1
A: JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,9722
Polymers38,5901
Non-polymers3821
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
2
B: JAK2


Theoretical massNumber of molelcules
Total (without water)38,5901
Polymers38,5901
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)102.757, 93.129, 123.269
Angle α, β, γ (deg.)90.00, 146.58, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein JAK2


Mass: 38589.648 Da / Num. of mol.: 2 / Fragment: KINASE DOMAIN, RESIDUES 835-1132
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PFASTBAC / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: O60674, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-L0I / 4-[(2-{4-[(CYCLOPROPYLCARBAMOYL)AMINO]-1H-PYRAZOL-3-YL}-1H-BENZIMIDAZOL-6-YL)METHYL]MORPHOLIN-4-IUM


Mass: 382.440 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H24N7O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 131 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.36 Å3/Da / Density % sol: 47.56 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Wavelength: 1.5418
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.6→29.72 Å / Num. obs: 18561 / % possible obs: 99 % / Observed criterion σ(I): 2 / Redundancy: 2.18 % / Rmerge(I) obs: 0.07 / Net I/σ(I): 8.3

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Processing

SoftwareName: REFMAC / Version: 5.2.0019F / Classification: refinement
RefinementMethod to determine structure: OTHER
Starting model: NONE

Resolution: 2.6→29.72 Å / Cor.coef. Fo:Fc: 0.932 / Cor.coef. Fo:Fc free: 0.863 / SU B: 14.815 / SU ML: 0.314 / Cross valid method: THROUGHOUT / ESU R Free: 0.403 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.295 992 5.1 %RANDOM
Rwork0.204 ---
obs0.209 18561 98.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 28.72 Å2
Baniso -1Baniso -2Baniso -3
1-0.47 Å20 Å20.29 Å2
2---0.34 Å20 Å2
3---0.35 Å2
Refinement stepCycle: LAST / Resolution: 2.6→29.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4748 0 28 131 4907
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0224882
X-RAY DIFFRACTIONr_bond_other_d0.0010.023448
X-RAY DIFFRACTIONr_angle_refined_deg1.4481.986579
X-RAY DIFFRACTIONr_angle_other_deg0.90638377
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7745568
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.63724.233258
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.00615.113929
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.3231534
X-RAY DIFFRACTIONr_chiral_restr0.0850.2684
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.025330
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02990
X-RAY DIFFRACTIONr_nbd_refined0.2160.21161
X-RAY DIFFRACTIONr_nbd_other0.1940.23638
X-RAY DIFFRACTIONr_nbtor_refined0.1830.22365
X-RAY DIFFRACTIONr_nbtor_other0.0880.22692
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1480.265
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1540.223
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1820.277
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1820.24
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.05852848
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.08864612
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it0.08562034
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it0.1137.51964
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.6→2.67 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.328 48
Rwork0.224 1366

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