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- PDB-7xc1: Crystal structure of ERK2 with an allosteric inhibitor 3 -

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Basic information

Entry
Database: PDB / ID: 7xc1
TitleCrystal structure of ERK2 with an allosteric inhibitor 3
ComponentsMitogen-activated protein kinase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Protein kinase MAPK Inhibitor / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


phospho-PLA2 pathway / interleukin-34-mediated signaling pathway / Signaling by MAPK mutants / RAF-independent MAPK1/3 activation / Suppression of apoptosis / Gastrin-CREB signalling pathway via PKC and MAPK / Signaling by Activin / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / cytosine metabolic process ...phospho-PLA2 pathway / interleukin-34-mediated signaling pathway / Signaling by MAPK mutants / RAF-independent MAPK1/3 activation / Suppression of apoptosis / Gastrin-CREB signalling pathway via PKC and MAPK / Signaling by Activin / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / cytosine metabolic process / response to epidermal growth factor / Signaling by NODAL / ERKs are inactivated / Signaling by MAP2K mutants / RSK activation / Golgi Cisternae Pericentriolar Stack Reorganization / Regulation of the apoptosome activity / positive regulation of macrophage proliferation / regulation of cellular pH / outer ear morphogenesis / Signaling by LTK in cancer / regulation of Golgi inheritance / positive regulation of peptidyl-threonine phosphorylation / ERBB signaling pathway / labyrinthine layer blood vessel development / mammary gland epithelial cell proliferation / trachea formation / Negative feedback regulation of MAPK pathway / regulation of early endosome to late endosome transport / IFNG signaling activates MAPKs / regulation of stress-activated MAPK cascade / Frs2-mediated activation / ERBB2-ERBB3 signaling pathway / positive regulation of macrophage chemotaxis / Activation of the AP-1 family of transcription factors / regulation of cytoskeleton organization / ERK/MAPK targets / RUNX2 regulates osteoblast differentiation / response to exogenous dsRNA / MAPK1 (ERK2) activation / lung morphogenesis / face development / pseudopodium / Bergmann glial cell differentiation / positive regulation of telomere maintenance / Recycling pathway of L1 / thyroid gland development / Advanced glycosylation endproduct receptor signaling / peptidyl-threonine phosphorylation / MAP kinase activity / regulation of ossification / negative regulation of cell differentiation / Regulation of HSF1-mediated heat shock response / RHO GTPases Activate NADPH Oxidases / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / mitogen-activated protein kinase / RHO GTPases Activate WASPs and WAVEs / Signal attenuation / phosphatase binding / Growth hormone receptor signaling / Schwann cell development / Estrogen-stimulated signaling through PRKCZ / stress-activated MAPK cascade / Nuclear events stimulated by ALK signaling in cancer / NPAS4 regulates expression of target genes / ERK1 and ERK2 cascade / phosphotyrosine residue binding / myelination / Transcriptional and post-translational regulation of MITF-M expression and activity / NCAM signaling for neurite out-growth / RNA polymerase II CTD heptapeptide repeat kinase activity / insulin-like growth factor receptor signaling pathway / ESR-mediated signaling / lipopolysaccharide-mediated signaling pathway / cellular response to amino acid starvation / thymus development / Regulation of PTEN gene transcription / Signal transduction by L1 / B cell receptor signaling pathway / response to nicotine / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / Negative regulation of FGFR3 signaling / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / Downregulation of SMAD2/3:SMAD4 transcriptional activity / Negative regulation of FGFR1 signaling / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / positive regulation of cholesterol biosynthetic process / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / Oncogene Induced Senescence / regulation of protein stability / caveola / Regulation of actin dynamics for phagocytic cup formation / epidermal growth factor receptor signaling pathway / long-term synaptic potentiation / chemotaxis / Interferon gamma signaling
Similarity search - Function
Mitogen-activated protein (MAP) kinase, ERK1/2 / 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. ...Mitogen-activated protein (MAP) kinase, ERK1/2 / 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-5ID / Chem-B8Z / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.09 Å
AuthorsYoshida, M. / Kinoshita, T.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: To Be Published
Title: Structural basis for ERK2 allosteric inhibitors.
Authors: Yoshida, M. / Kinoshita, T.
History
DepositionMar 22, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 22, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Mitogen-activated protein kinase 1
B: Mitogen-activated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)86,79212
Polymers84,6212
Non-polymers2,17110
Water3,207178
1
A: Mitogen-activated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,6677
Polymers42,3101
Non-polymers1,3566
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area160 Å2
ΔGint-12 kcal/mol
Surface area16840 Å2
MethodPISA
2
B: Mitogen-activated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,1255
Polymers42,3101
Non-polymers8154
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area16530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.653, 82.653, 275.074
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212
Space group name HallP4abw2nw
Symmetry operation#1: x,y,z
#2: -y+1/2,x+1/2,z+1/4
#3: y+1/2,-x+1/2,z+3/4
#4: x+1/2,-y+1/2,-z+3/4
#5: -x+1/2,y+1/2,-z+1/4
#6: -x,-y,z+1/2
#7: y,x,-z
#8: -y,-x,-z+1/2

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Mitogen-activated protein kinase 1 / MAP kinase 1 / MAPK 1 / ERT1 / Extracellular signal-regulated kinase 2 / ERK-2 / MAP kinase isoform ...MAP kinase 1 / MAPK 1 / ERT1 / Extracellular signal-regulated kinase 2 / ERK-2 / MAP kinase isoform p42 / p42-MAPK / Mitogen-activated protein kinase 2 / MAP kinase 2 / MAPK 2


Mass: 42310.410 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK1, ERK2, PRKM1, PRKM2 / Production host: Escherichia coli BL21 (bacteria)
References: UniProt: P28482, mitogen-activated protein kinase

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Non-polymers , 6 types, 188 molecules

#2: Chemical ChemComp-5ID / (2R,3R,4S,5R)-2-(4-AMINO-5-IODO-7H-PYRROLO[2,3-D]PYRIMIDIN-7-YL)-5-(HYDROXYMETHYL)TETRAHYDROFURAN-3,4-DIOL / 5-IODOTUBERCIDIN


Mass: 392.150 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C11H13IN4O4
#3: Chemical ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES


Mass: 238.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-B8Z / ~{N}-(5,6-dimethoxy-1,3-benzothiazol-2-yl)-2-[(4-fluoranylphenoxy)methyl]-1,3-thiazole-4-carboxamide


Mass: 445.487 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H16FN3O4S2
#6: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 178 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN

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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: 2.78 Å3/Da / Density % sol: 55.69 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 10% PEG3350 0.1M HEPES pH 7.5 0.25M L-proline glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL44XU / Wavelength: 0.9 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 16, 2021
RadiationMonochromator: mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9 Å / Relative weight: 1
ReflectionResolution: 2.09→41.33 Å / Num. obs: 57640 / % possible obs: 99.9 % / Redundancy: 13.4 % / Biso Wilson estimate: 51.7 Å2 / CC1/2: 0.99 / Net I/σ(I): 16.8
Reflection shellResolution: 2.09→2.16 Å / Num. unique obs: 57581 / CC1/2: 0.46 / % possible all: 99.6

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4QP1

4qp1


Resolution: 2.09→41.33 Å / SU ML: 0.3605 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 32.6048
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.271 2873 5 %
Rwork0.2296 54590 -
obs0.2317 57463 99.62 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 66.72 Å2
Refinement stepCycle: LAST / Resolution: 2.09→41.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5703 0 129 178 6010
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00985972
X-RAY DIFFRACTIONf_angle_d1.00918099
X-RAY DIFFRACTIONf_chiral_restr0.0526874
X-RAY DIFFRACTIONf_plane_restr0.01091025
X-RAY DIFFRACTIONf_dihedral_angle_d16.51622248
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.09-2.120.43141340.4052497X-RAY DIFFRACTION96.69
2.12-2.160.41741330.39462506X-RAY DIFFRACTION98.8
2.16-2.20.40411350.37712540X-RAY DIFFRACTION99.63
2.2-2.240.331350.34922563X-RAY DIFFRACTION99.56
2.24-2.290.37321330.32762546X-RAY DIFFRACTION99.63
2.29-2.340.36081320.31342547X-RAY DIFFRACTION99.55
2.34-2.390.32111350.29332554X-RAY DIFFRACTION99.67
2.39-2.450.31811360.2722575X-RAY DIFFRACTION99.78
2.45-2.520.33621350.2692568X-RAY DIFFRACTION99.85
2.52-2.590.34871370.27352604X-RAY DIFFRACTION99.93
2.59-2.680.31350.27412564X-RAY DIFFRACTION99.93
2.68-2.770.30951340.26822580X-RAY DIFFRACTION99.63
2.77-2.880.32411350.27862565X-RAY DIFFRACTION99.96
2.88-3.010.31011370.25182614X-RAY DIFFRACTION99.89
3.01-3.170.2961380.24082619X-RAY DIFFRACTION99.96
3.17-3.370.26721370.23962590X-RAY DIFFRACTION99.93
3.37-3.630.2671380.22882642X-RAY DIFFRACTION99.93
3.63-40.27461390.19522639X-RAY DIFFRACTION100
4-4.570.22331400.18872675X-RAY DIFFRACTION99.96
4.57-5.760.24261430.19852710X-RAY DIFFRACTION100
5.76-41.330.22421520.19862892X-RAY DIFFRACTION99.8

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