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- PDB-6hkm: Crystal structure of Compound 1 with ERK5 -

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Basic information

Entry
Database: PDB / ID: 6hkm
TitleCrystal structure of Compound 1 with ERK5
ComponentsMitogen-activated protein kinase 7
KeywordsTRANSFERASE / ERK5 KINASE / IMMUNE SYSTEM
Function / homology
Function and homology information


Signalling to ERK5 / negative regulation of response to cytokine stimulus / negative regulation of heterotypic cell-cell adhesion / calcineurin-NFAT signaling cascade / cellular response to laminar fluid shear stress / Gastrin-CREB signalling pathway via PKC and MAPK / ERKs are inactivated / enzyme inhibitor activity / mitogen-activated protein kinase binding / negative regulation of calcineurin-NFAT signaling cascade ...Signalling to ERK5 / negative regulation of response to cytokine stimulus / negative regulation of heterotypic cell-cell adhesion / calcineurin-NFAT signaling cascade / cellular response to laminar fluid shear stress / Gastrin-CREB signalling pathway via PKC and MAPK / ERKs are inactivated / enzyme inhibitor activity / mitogen-activated protein kinase binding / negative regulation of calcineurin-NFAT signaling cascade / ERK/MAPK targets / negative regulation of smooth muscle cell apoptotic process / 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / PML body / cellular response to growth factor stimulus / negative regulation of inflammatory response / cellular response to hydrogen peroxide / 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 / cytoplasm / cytosol
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-G92 / Mitogen-activated protein kinase 7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.47 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
Revision 1.1May 15, 2024Group: Advisory / Data collection ...Advisory / Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_contact_author / pdbx_unobs_or_zero_occ_atoms
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_contact_author.email

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)40,1872
Polymers39,7261
Non-polymers4611
Water59433
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area16480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)92.477, 92.477, 108.450
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: 39725.750 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-G92 / [4-(6,7-dimethoxyquinazolin-4-yl)piperidin-1-yl]-[4-(trifluoromethyloxy)phenyl]methanone


Mass: 461.434 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H22F3N3O4
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 33 / 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: 3.01 Å3/Da / Density % sol: 59.21 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 11% PEG 4000, 100mM MgCl2, 160mM sodium formate, 100mM MES pH 6.75, 10mM Tris pH 8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.999999701977 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 26, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999999701977 Å / Relative weight: 1
ReflectionResolution: 2.47→70.37 Å / Num. obs: 17105 / % possible obs: 96.8 % / Redundancy: 4.6 % / Rmerge(I) obs: 0.053 / Net I/σ(I): 16.5
Reflection shellResolution: 2.47→2.71 Å / Redundancy: 4.7 % / Rmerge(I) obs: 0.429 / % possible all: 93.2

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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: 2.47→70.37 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.857 / SU B: 22.987 / SU ML: 0.25 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.394 / ESU R Free: 0.291
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28 1008 5.9 %RANDOM
Rwork0.2182 ---
obs0.2218 16094 97.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 114.57 Å2 / Biso mean: 34.414 Å2 / Biso min: 13.28 Å2
Baniso -1Baniso -2Baniso -3
1-0.54 Å20 Å20 Å2
2--0.54 Å2-0 Å2
3----1.09 Å2
Refinement stepCycle: final / Resolution: 2.47→70.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2645 0 33 33 2711
Biso mean--57.83 53.05 -
Num. residues----327
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0192726
X-RAY DIFFRACTIONr_bond_other_d0.0020.022594
X-RAY DIFFRACTIONr_angle_refined_deg1.2081.9743703
X-RAY DIFFRACTIONr_angle_other_deg0.93435924
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6465330
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.71722.683123
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.03615440
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.9341523
X-RAY DIFFRACTIONr_chiral_restr0.0680.2407
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0213055
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02646
LS refinement shellResolution: 2.47→2.534 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.351 86 -
Rwork0.321 1120 -
all-1206 -
obs--96.25 %
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)
18.6321-2.369-3.49651.91031.98252.9574-0.17160.6602-1.1036-0.1002-0.09210.55170.2592-0.32080.26370.2479-0.0736-0.16230.3312-0.05850.4152-5.306-36.208-12.097
23.05-0.0703-1.63593.33880.61346.3280.332-0.68690.22330.47960.0529-0.0922-0.00310.9186-0.3850.1799-0.098-0.0080.453-0.14820.062217.858-32.9631.212
38.33720.0376-0.6325.2581.86673.88050.25920.57180.1143-0.5912-0.15180.0177-0.3308-0.0989-0.10730.20610.0589-0.02020.2948-0.00650.0492-8.214-23.739-12.313
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 139
2X-RAY DIFFRACTION2A140 - 364
3X-RAY DIFFRACTION3A365 - 400

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