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- PDB-4mq2: The crystal structure of DYRK1a with a bound pyrido[2,3-d]pyrimid... -

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Basic information

Entry
Database: PDB / ID: 4mq2
TitleThe crystal structure of DYRK1a with a bound pyrido[2,3-d]pyrimidine inhibitor
ComponentsDual specificity tyrosine-phosphorylation-regulated kinase 1ADYRK1A
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / dyrk1a / dyrk1b / kinase / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


histone H3T45 kinase activity / positive regulation of protein deacetylation / peptidyl-serine autophosphorylation / negative regulation of DNA methylation-dependent heterochromatin formation / dual-specificity kinase / [RNA-polymerase]-subunit kinase / negative regulation of microtubule polymerization / tau-protein kinase activity / negative regulation of mRNA splicing, via spliceosome / negative regulation of DNA damage response, signal transduction by p53 class mediator ...histone H3T45 kinase activity / positive regulation of protein deacetylation / peptidyl-serine autophosphorylation / negative regulation of DNA methylation-dependent heterochromatin formation / dual-specificity kinase / [RNA-polymerase]-subunit kinase / negative regulation of microtubule polymerization / tau-protein kinase activity / negative regulation of mRNA splicing, via spliceosome / negative regulation of DNA damage response, signal transduction by p53 class mediator / amyloid-beta formation / G0 and Early G1 / peptidyl-tyrosine autophosphorylation / cytoskeletal protein binding / protein serine/threonine/tyrosine kinase activity / tubulin binding / RNA polymerase II CTD heptapeptide repeat kinase activity / positive regulation of RNA splicing / peptidyl-threonine phosphorylation / tau protein binding / non-membrane spanning protein tyrosine kinase activity / circadian rhythm / peptidyl-tyrosine phosphorylation / : / nervous system development / actin binding / peptidyl-serine phosphorylation / protein tyrosine kinase activity / protein autophosphorylation / transcription coactivator activity / cytoskeleton / protein kinase activity / nuclear speck / ribonucleoprotein complex / axon / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / dendrite / positive regulation of DNA-templated transcription / nucleoplasm / ATP binding / identical protein binding / nucleus / cytoplasm
Similarity search - Function
Dual specificity tyrosine-phosphorylation-regulated kinase 1A/1B, catalytic domain / 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 ...Dual specificity tyrosine-phosphorylation-regulated kinase 1A/1B, catalytic domain / 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-2C4 / Dual specificity tyrosine-phosphorylation-regulated kinase 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsLukacs, C.M. / Janson, C.A. / Garvie, C. / Liang, L.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Pyrido[2,3-d]pyrimidines: Discovery and preliminary SAR of a novel series of DYRK1B and DYRK1A inhibitors.
Authors: Anderson, K. / Chen, Y. / Chen, Z. / Dominique, R. / Glenn, K. / He, Y. / Janson, C. / Luk, K.C. / Lukacs, C. / Polonskaia, A. / Qiao, Q. / Railkar, A. / Rossman, P. / Sun, H. / Xiang, Q. / ...Authors: Anderson, K. / Chen, Y. / Chen, Z. / Dominique, R. / Glenn, K. / He, Y. / Janson, C. / Luk, K.C. / Lukacs, C. / Polonskaia, A. / Qiao, Q. / Railkar, A. / Rossman, P. / Sun, H. / Xiang, Q. / Vilenchik, M. / Wovkulich, P. / Zhang, X.
History
DepositionSep 15, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 11, 2013Provider: repository / Type: Initial release
Revision 1.1Dec 18, 2013Group: Database references
Revision 1.2Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Dec 6, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
B: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
C: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
D: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)171,79119
Polymers168,3264
Non-polymers3,46515
Water2,180121
1
A: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,1396
Polymers42,0821
Non-polymers1,0575
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,2357
Polymers42,0821
Non-polymers1,1546
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,7093
Polymers42,0821
Non-polymers6272
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Dual specificity tyrosine-phosphorylation-regulated kinase 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,7093
Polymers42,0821
Non-polymers6272
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)264.097, 65.161, 138.426
Angle α, β, γ (deg.)90.00, 115.01, 90.00
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(-0.605305, -0.795178, -0.036024), (-0.795363, 0.602406, 0.067114), (-0.031666, 0.069277, -0.997095)19.81938, 14.32428, -103.90282
3given(0.833953, 0.477848, -0.276013), (0.486012, -0.872905, -0.042769), (-0.26137, -0.098478, -0.960202)11.45065, -0.8031, -44.4834
4given(0.891535, -0.369992, -0.261289), (-0.381315, -0.924411, 0.007918), (-0.244467, 0.092574, -0.965228)50.64078, 1.25081, -80.59571

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Components

#1: Protein
Dual specificity tyrosine-phosphorylation-regulated kinase 1A / DYRK1A / Dual specificity YAK1-related kinase / HP86 / Protein kinase minibrain homolog / MNBH / hMNB


Mass: 42081.535 Da / Num. of mol.: 4 / Fragment: UNP residues 127-485
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DYRK1A, DYRK, MNB, MNBH / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)-R3-pRARE2 / References: UniProt: Q13627, dual-specificity kinase
#2: Chemical
ChemComp-2C4 / methyl 4-chloro-3-{[(2-methoxy-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)carbonyl]amino}benzoate


Mass: 388.762 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H13ClN4O5
#3: Chemical
ChemComp-1PE / PENTAETHYLENE GLYCOL / PEG400 / Polyethylene glycol


Mass: 238.278 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C10H22O6 / Comment: precipitant*YM
#4: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 121 / 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: 3.21 Å3/Da / Density % sol: 61.64 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 15% PEG 300, 0.1M LiSO4, 0.1M Tris, pH 8.5, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.97929 Å
DetectorType: RAYONIX MX225HE / Detector: CCD / Date: Dec 3, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97929 Å / Relative weight: 1
ReflectionResolution: 2.8→50 Å / Num. obs: 53115 / % possible obs: 99.9 % / Redundancy: 3.8 % / Biso Wilson estimate: 73 Å2 / Rmerge(I) obs: 0.099 / Net I/σ(I): 8.9

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Processing

Software
NameVersionClassification
REFMAC5.7.0032refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 2vx3

2vx3


Resolution: 2.8→36.78 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.899 / SU B: 12.571 / SU ML: 0.247 / Cross valid method: THROUGHOUT / ESU R: 0.784 / ESU R Free: 0.347 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25754 2652 5 %RANDOM
Rwork0.18991 ---
obs0.19327 50463 99.92 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 53.443 Å2
Baniso -1Baniso -2Baniso -3
1-0.72 Å2-0 Å2-0.6 Å2
2--0.08 Å20 Å2
3----0.36 Å2
Refinement stepCycle: LAST / Resolution: 2.8→36.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10918 0 226 121 11265
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.01911409
X-RAY DIFFRACTIONr_bond_other_d0.0020.0210825
X-RAY DIFFRACTIONr_angle_refined_deg1.611.98715405
X-RAY DIFFRACTIONr_angle_other_deg0.8663.00624838
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.60551343
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.42323.916526
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.727151946
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.1251564
X-RAY DIFFRACTIONr_chiral_restr0.0850.21638
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.02112673
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022687
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.7645.3395402
X-RAY DIFFRACTIONr_mcbond_other3.7645.3395401
X-RAY DIFFRACTIONr_mcangle_it5.7947.9896732
X-RAY DIFFRACTIONr_mcangle_other5.7937.996733
X-RAY DIFFRACTIONr_scbond_it3.6565.5786007
X-RAY DIFFRACTIONr_scbond_other3.6555.5786008
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.7058.2718673
X-RAY DIFFRACTIONr_long_range_B_refined8.01542.76213154
X-RAY DIFFRACTIONr_long_range_B_other8.01742.7713142
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.8→2.873 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.367 196 -
Rwork0.284 3699 -
obs--99.92 %

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