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- PDB-6hkn: Crystal structure of Compound 35 with ERK5 -

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Basic information

Entry
Database: PDB / ID: 6hkn
TitleCrystal structure of Compound 35 with ERK5
ComponentsMitogen-activated protein kinase 7
KeywordsTRANSFERASE / ERK5 KINASE
Function / homology
Function and homology information


Signalling to ERK5 / negative regulation of response to cytokine stimulus / negative regulation of cyclic-nucleotide phosphodiesterase activity / negative regulation of heterotypic cell-cell adhesion / calcineurin-NFAT signaling cascade / negative regulation of smooth muscle cell apoptotic process / cellular response to laminar fluid shear stress / Gastrin-CREB signalling pathway via PKC and MAPK / ERKs are inactivated / mitogen-activated protein kinase binding ...Signalling to ERK5 / negative regulation of response to cytokine stimulus / negative regulation of cyclic-nucleotide phosphodiesterase activity / negative regulation of heterotypic cell-cell adhesion / calcineurin-NFAT signaling cascade / negative regulation of smooth muscle cell apoptotic process / cellular response to laminar fluid shear stress / Gastrin-CREB signalling pathway via PKC and MAPK / ERKs are inactivated / mitogen-activated protein kinase binding / negative regulation of calcineurin-NFAT signaling cascade / ERK/MAPK targets / cAMP-mediated signaling / RET signaling / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / MAP kinase activity / mitogen-activated protein kinase / regulation of angiogenesis / negative regulation of endothelial cell apoptotic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / cellular response to transforming growth factor beta stimulus / positive regulation of protein metabolic process / PML body / cellular response to hydrogen peroxide / cellular response to growth factor stimulus / negative regulation of inflammatory response / MAPK cascade / Senescence-Associated Secretory Phenotype (SASP) / cell differentiation / intracellular signal transduction / cell cycle / phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / signal transduction / positive regulation of transcription by RNA polymerase II / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
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 ...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-G9E / Mitogen-activated protein kinase 7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.33 Å
AuthorsNguyen, D. / Lemos, C. / Wortmann, L. / Eis, K. / Holton, S.J. / Boemer, U. / Lechner, C. / Prechtl, S. / Suelze, D. / Siegel, F. ...Nguyen, D. / Lemos, C. / Wortmann, L. / Eis, K. / Holton, S.J. / Boemer, U. / Lechner, C. / Prechtl, S. / Suelze, D. / Siegel, F. / Prinz, F. / Lesche, R. / Nicke, B. / Mumberg, D. / Bauser, M. / Haegebarth, A.
CitationJournal: J. Med. Chem. / Year: 2019
Title: Discovery and Characterization of the Potent and Highly Selective (Piperidin-4-yl)pyrido[3,2- d]pyrimidine Based in Vitro Probe BAY-885 for the Kinase ERK5.
Authors: Nguyen, D. / Lemos, C. / Wortmann, L. / Eis, K. / Holton, S.J. / Boemer, U. / Moosmayer, D. / Eberspaecher, U. / Weiske, J. / Lechner, C. / Prechtl, S. / Suelzle, D. / Siegel, F. / Prinz, F. ...Authors: Nguyen, D. / Lemos, C. / Wortmann, L. / Eis, K. / Holton, S.J. / Boemer, U. / Moosmayer, D. / Eberspaecher, U. / Weiske, J. / Lechner, C. / Prechtl, S. / Suelzle, D. / Siegel, F. / Prinz, F. / Lesche, R. / Nicke, B. / Nowak-Reppel, K. / Himmel, H. / Mumberg, D. / von Nussbaum, F. / Nising, C.F. / Bauser, M. / Haegebarth, A.
History
DepositionSep 7, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 27, 2019Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Mitogen-activated protein kinase 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,4682
Polymers39,0221
Non-polymers4461
Water1,76598
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area16310 Å2
MethodPISA
Unit cell
Length a, b, c (Å)92.488, 92.488, 113.585
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212

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Components

#1: Protein Mitogen-activated protein kinase 7 / MAPK 7 / Big MAP kinase 1 / BMK-1 / Extracellular signal-regulated kinase 5 / ERK-5


Mass: 39022.012 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK7, BMK1, ERK5, PRKM7 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q13164, mitogen-activated protein kinase
#2: Chemical ChemComp-G9E / [2-azanyl-4-(trifluoromethyloxy)phenyl]-[4-(7-methoxyquinazolin-4-yl)piperidin-1-yl]methanone


Mass: 446.422 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H21F3N4O3
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 98 / 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: 3.18 Å3/Da / Density % sol: 61.29 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 15% PEG 4000, 100mM MgCl2, 180mM Sodium formate, 100 mM MES pH 6.5, 10mM Tris pH 8.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99982 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Apr 5, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99982 Å / Relative weight: 1
ReflectionResolution: 2.33→71.72 Å / Num. obs: 21662 / % possible obs: 99.9 % / Redundancy: 5.5 % / Rmerge(I) obs: 0.051 / Net I/σ(I): 20.3
Reflection shellResolution: 2.33→2.58 Å / Redundancy: 5.5 % / Rmerge(I) obs: 0.446 / % possible all: 99.8

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Processing

Software
NameVersionClassification
Aimlessdata scaling
REFMAC5.8.0049refinement
PDB_EXTRACT3.24data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 2.33→71.72 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.928 / SU B: 14.256 / SU ML: 0.172 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.27 / ESU R Free: 0.219
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2491 1206 5.6 %RANDOM
Rwork0.2068 ---
obs0.2091 20456 99.87 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 91.25 Å2 / Biso mean: 34.764 Å2 / Biso min: 11.21 Å2
Baniso -1Baniso -2Baniso -3
1--0 Å2-0 Å20 Å2
2---0 Å2-0 Å2
3---0 Å2
Refinement stepCycle: final / Resolution: 2.33→71.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2701 0 32 98 2831
Biso mean--46.24 50.41 -
Num. residues----333
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0192766
X-RAY DIFFRACTIONr_bond_other_d0.0010.022643
X-RAY DIFFRACTIONr_angle_refined_deg1.1641.9753761
X-RAY DIFFRACTIONr_angle_other_deg2.53136041
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.945334
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.02822.72125
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.36715452
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.3761523
X-RAY DIFFRACTIONr_chiral_restr0.0670.2411
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0213105
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02656
LS refinement shellResolution: 2.33→2.391 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.392 89 -
Rwork0.294 1479 -
all-1568 -
obs--100 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
16.4913-1.7783-1.78061.17720.79171.77050.03060.3357-0.3513-0.2642-0.0910.19250.0653-0.22940.06040.2635-0.01-0.04480.260.02610.0432-0.586-31.758-12.619
22.4534-0.4858-0.52472.14730.76053.14970.0441-0.30350.10750.22990.0565-0.04510.03660.2974-0.10050.2032-0.0654-0.00370.2568-0.01420.006913.949-33.944-0.271
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 117
2X-RAY DIFFRACTION1A343 - 400
3X-RAY DIFFRACTION2A118 - 342

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