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- PDB-5o7i: ERK5 in complex with a pyrrole inhibitor -

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Basic information

Entry
Database: PDB / ID: 5o7i
TitleERK5 in complex with a pyrrole inhibitor
ComponentsMitogen-activated protein kinase 7
KeywordsTRANSFERASE / KINASE / INHIBITOR / PYRROLE
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 / cellular response to growth factor stimulus / PML body / 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 / cytosol / cytoplasm
Similarity search - Function
Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / 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
Similarity search - Domain/homology
Chem-9N8 / Mitogen-activated protein kinase 7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.38 Å
AuthorsTucker, J.A. / Heptinstall, A. / Myers, S.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Medical Research Council (United Kingdom)RES/0190/7680 United Kingdom
CitationJournal: Eur.J.Med.Chem. / Year: 2019
Title: Identification of a novel orally bioavailable ERK5 inhibitor with selectivity over p38 alpha and BRD4.
Authors: Myers, S.M. / Miller, D.C. / Molyneux, L. / Arasta, M. / Bawn, R.H. / Blackburn, T.J. / Cook, S.J. / Edwards, N. / Endicott, J.A. / Golding, B.T. / Griffin, R.J. / Hammonds, T. / Hardcastle, ...Authors: Myers, S.M. / Miller, D.C. / Molyneux, L. / Arasta, M. / Bawn, R.H. / Blackburn, T.J. / Cook, S.J. / Edwards, N. / Endicott, J.A. / Golding, B.T. / Griffin, R.J. / Hammonds, T. / Hardcastle, I.R. / Harnor, S.J. / Heptinstall, A.B. / Lochhead, P.A. / Martin, M.P. / Martin, N.C. / Newell, D.R. / Owen, P.J. / Pang, L.C. / Reuillon, T. / Rigoreau, L.J.M. / Thomas, H.D. / Tucker, J.A. / Wang, L.Z. / Wong, A.C. / Noble, M.E.M. / Wedge, S.R. / Cano, C.
History
DepositionJun 8, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 20, 2018Provider: repository / Type: Initial release
Revision 1.1Jun 5, 2019Group: Data collection / Database references / Category: citation / pdbx_database_proc
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Jun 26, 2019Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3Jan 17, 2024Group: 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)41,5243
Polymers41,0571
Non-polymers4662
Water1,964109
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area160 Å2
ΔGint1 kcal/mol
Surface area16030 Å2
MethodPISA
Unit cell
Length a, b, c (Å)93.910, 93.910, 113.748
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 41057.234 Da / Num. of mol.: 1 / Fragment: UNP residues 46-402
Source method: isolated from a genetically manipulated source
Details: synthetic DNA (Life Technologies) / Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK7, BMK1, ERK5, PRKM7 / Plasmid: pFastBac HT A / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q13164, mitogen-activated protein kinase
#2: Chemical ChemComp-9N8 / 4-(2-bromanyl-6-fluoranyl-phenyl)carbonyl-~{N}-pyridin-3-yl-1~{H}-pyrrole-2-carboxamide


Mass: 388.191 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H11BrFN3O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 109 / 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: 3.05 Å3/Da / Density % sol: 59.73 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: 5 % (v/v) PEG 6000, 0.1 M MES (pH 6.0), 5 mM DTT

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 1.37852 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 5, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.37852 Å / Relative weight: 1
ReflectionResolution: 2.38→48.65 Å / Num. obs: 21010 / % possible obs: 99.94 % / Redundancy: 14.2 % / Biso Wilson estimate: 61.89 Å2 / Rmerge(I) obs: 0.15 / Net I/σ(I): 12.5
Reflection shellResolution: 2.38→2.5 Å / Redundancy: 15 % / Rmerge(I) obs: 1.29 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 2719 / % possible all: 99.56

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Processing

Software
NameVersionClassification
BUSTER2.10.2refinement
XDSdata reduction
Aimless0.5.17data scaling
MOLREP11.4.04phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5BYZ

5byz


Resolution: 2.38→48.65 Å / Cor.coef. Fo:Fc: 0.9449 / Cor.coef. Fo:Fc free: 0.9071 / SU R Cruickshank DPI: 0.239 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.248 / SU Rfree Blow DPI: 0.196 / SU Rfree Cruickshank DPI: 0.194
RfactorNum. reflection% reflectionSelection details
Rfree0.2203 1021 4.86 %RANDOM
Rwork0.1805 ---
obs0.1824 21010 99.94 %-
Displacement parametersBiso mean: 59.88 Å2
Baniso -1Baniso -2Baniso -3
1--3.8356 Å20 Å20 Å2
2---3.8356 Å20 Å2
3---7.6713 Å2
Refine analyzeLuzzati coordinate error obs: 0.275 Å
Refinement stepCycle: 1 / Resolution: 2.38→48.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2764 0 28 109 2901
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012884HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.043934HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d994SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes60HARMONIC2
X-RAY DIFFRACTIONt_gen_planes462HARMONIC5
X-RAY DIFFRACTIONt_it2884HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.93
X-RAY DIFFRACTIONt_other_torsion17.89
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion366SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies6HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3365SEMIHARMONIC4
LS refinement shellResolution: 2.38→2.5 Å / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.2683 124 4.56 %
Rwork0.2074 2595 -
all0.2102 2719 -
obs--99.56 %
Refinement TLS params.Method: refined / Origin x: 33.7134 Å / Origin y: -7.8706 Å / Origin z: 5.448 Å
111213212223313233
T-0.0871 Å2-0.0661 Å2-0.0023 Å2--0.0444 Å20.0061 Å2---0.06 Å2
L1.1688 °2-0.5669 °20.3533 °2-1.6625 °2-0.7005 °2--2.2676 °2
S-0.0202 Å °0.0023 Å °0.039 Å °0.0108 Å °0.0895 Å °0.0521 Å °0.1844 Å °-0.1137 Å °-0.0693 Å °
Refinement TLS groupSelection details: { A|* }

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