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- PDB-8pt3: ERK2 covelently bound to RU77 cyclohexenone based inhibitor -

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Basic information

Entry
Database: PDB / ID: 8pt3
TitleERK2 covelently bound to RU77 cyclohexenone based inhibitor
ComponentsMitogen-activated protein kinase 1
KeywordsSIGNALING PROTEIN / MAPK kinase / MAPK / inhibitor / covalent / ERK2 / Michael acceptor warhead
Function / homology
Function and homology information


phospho-PLA2 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 / Signaling by MAP2K mutants ...phospho-PLA2 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 / Signaling by MAP2K mutants / Signaling by NODAL / ERKs are inactivated / response to epidermal growth factor / 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 / labyrinthine layer blood vessel development / ERBB signaling pathway / mammary gland epithelial cell proliferation / trachea formation / Negative feedback regulation of MAPK pathway / positive regulation of peptidyl-threonine phosphorylation / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / IFNG signaling activates MAPKs / Frs2-mediated activation / ERBB2-ERBB3 signaling pathway / MAPK1 (ERK2) activation / 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 / face development / lung morphogenesis / positive regulation of telomere maintenance / Recycling pathway of L1 / pseudopodium / Bergmann glial cell differentiation / androgen receptor signaling pathway / thyroid gland development / steroid hormone receptor signaling pathway / Advanced glycosylation endproduct receptor signaling / RHO GTPases Activate NADPH Oxidases / MAP kinase activity / negative regulation of cell differentiation / regulation of ossification / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / Regulation of HSF1-mediated heat shock response / RHO GTPases Activate WASPs and WAVEs / JUN kinase activity / mitogen-activated protein kinase / Signal attenuation / Estrogen-stimulated signaling through PRKCZ / phosphatase binding / Schwann cell development / Growth hormone receptor signaling / progesterone receptor signaling pathway / stress-activated MAPK cascade / Nuclear events stimulated by ALK signaling in cancer / NPAS4 regulates expression of target genes / phosphotyrosine residue binding / myelination / RNA polymerase II CTD heptapeptide repeat kinase activity / peptidyl-threonine phosphorylation / Transcriptional and post-translational regulation of MITF-M expression and activity / NCAM signaling for neurite out-growth / ERK1 and ERK2 cascade / cellular response to amino acid starvation / insulin-like growth factor receptor signaling pathway / lipopolysaccharide-mediated signaling pathway / ESR-mediated signaling / thymus development / Regulation of PTEN gene transcription / Signal transduction by L1 / B cell receptor signaling pathway / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / response to nicotine / 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 / positive regulation of cholesterol biosynthetic process / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / regulation of protein stability / Oncogene Induced Senescence / caveola / Regulation of actin dynamics for phagocytic cup formation / long-term synaptic potentiation
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
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / : / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsSok, P. / Poti, A. / Remenyi, A.
Funding support Hungary, 1items
OrganizationGrant numberCountry
National Research Development and Innovation Office (NKFIH)KKP 126963 Hungary
CitationJournal: Nat Commun / Year: 2024
Title: Targeting a key protein-protein interaction surface on mitogen-activated protein kinases by a precision-guided warhead scaffold.
Authors: Poti, A.L. / Balint, D. / Alexa, A. / Sok, P. / Ozsvath, K. / Albert, K. / Turczel, G. / Magyari, S. / Ember, O. / Papp, K. / Kiraly, S.B. / Imre, T. / Nemeth, K. / Kurtan, T. / Gogl, G. / ...Authors: Poti, A.L. / Balint, D. / Alexa, A. / Sok, P. / Ozsvath, K. / Albert, K. / Turczel, G. / Magyari, S. / Ember, O. / Papp, K. / Kiraly, S.B. / Imre, T. / Nemeth, K. / Kurtan, T. / Gogl, G. / Varga, S. / Soos, T. / Remenyi, A.
History
DepositionJul 13, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 24, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 16, 2024Group: Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / pdbx_entry_details / pdbx_modification_feature
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)42,8246
Polymers41,7471
Non-polymers1,0775
Water2,738152
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: surface plasmon resonance
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)41.937, 78.471, 122.744
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#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: 41746.941 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: The dephosphorylated inactive ERK2 kinase with RU77 covalent inhibitor at the docking groove
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK1, ERK2, PRKM1, PRKM2 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P28482, mitogen-activated protein kinase
#2: Chemical ChemComp-D7O / ~{O}3-~{tert}-butyl ~{O}1-methyl (1~{S},3~{S},5~{R})-6-methylidene-4-oxidanylidene-bicyclo[3.2.1]octane-1,3-dicarboxylate


Mass: 294.343 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H22O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-ANP / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER


Mass: 506.196 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H17N6O12P3 / Comment: AMP-PNP, energy-carrying molecule analogue*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 152 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.49 Å3/Da / Density % sol: 50.7 % / Description: rhomboid
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: 10% PEG8000, 0.1 M Tris pH 8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, EMBL c/o DESY / Beamline: P14 (MX2) / Wavelength: 0.9763 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Dec 15, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 1.8→48.34 Å / Num. obs: 38481 / % possible obs: 100 % / Redundancy: 13.3 % / CC1/2: 1 / Rmerge(I) obs: 0.065 / Rpim(I) all: 0.019 / Rrim(I) all: 0.068 / Χ2: 1.02 / Net I/σ(I): 20.3
Reflection shellResolution: 1.8→1.84 Å / % possible obs: 100 % / Redundancy: 13.2 % / Rmerge(I) obs: 2.151 / Num. measured all: 29460 / Num. unique obs: 2229 / CC1/2: 0.56 / Rpim(I) all: 0.609 / Rrim(I) all: 2.237 / Χ2: 1.03 / Net I/σ(I) obs: 1.4

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Processing

Software
NameVersionClassification
PHENIX1.20.1refinement
XSCALEdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→48.34 Å / SU ML: 0.21 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.4 / Stereochemistry target values: ML
Details: ideal bond length restraints were used for the HIS125-RU77 covalent bond
RfactorNum. reflection% reflection
Rfree0.2222 2000 5.21 %
Rwork0.1867 --
obs0.1885 38411 99.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.8→48.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2784 0 70 152 3006
Refine LS restraintsType: bond length HIS-RU77 / Dev ideal target: 1.5
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8-1.850.29441390.26642546X-RAY DIFFRACTION100
1.85-1.890.30871420.25192567X-RAY DIFFRACTION100
1.89-1.950.27081400.24192558X-RAY DIFFRACTION100
1.95-2.010.25651420.22222576X-RAY DIFFRACTION100
2.01-2.090.25451400.19572549X-RAY DIFFRACTION100
2.09-2.170.24591420.19252582X-RAY DIFFRACTION100
2.17-2.270.23851400.19122553X-RAY DIFFRACTION100
2.27-2.390.23581410.19442580X-RAY DIFFRACTION100
2.39-2.540.26931440.20752608X-RAY DIFFRACTION100
2.54-2.730.24391420.20362576X-RAY DIFFRACTION100
2.73-3.010.21841440.20372637X-RAY DIFFRACTION100
3.01-3.440.22551440.19242624X-RAY DIFFRACTION100
3.44-4.340.19271460.15762659X-RAY DIFFRACTION100
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)
13.37611.88030.39094.10551.96572.21070.07780.0750.1379-0.1465-0.27230.534-0.3125-0.46130.20990.19390.0516-0.01530.3775-0.01890.2538-22.6948-12.3132.647
21.11030.2768-0.47682.2475-0.70793.24850.07220.0019-0.07550.1738-0.0305-0.03090.08620.0681-0.03340.21910.0136-0.01740.2445-0.03590.2848-15.0952-16.87616.829
35.5019-0.259-0.01082.40551.41935.72190.0271-0.23490.66930.2466-0.0858-0.2652-0.66020.43080.12620.3673-0.052-0.05420.33470.00060.3678-10.1408-9.175923.048
42.5161-0.50930.62592.81371.26983.5724-0.0434-0.24950.2170.5702-0.0124-0.01260.12730.14620.04940.4567-0.04950.0130.2831-0.00450.255-17.4961-12.120739.9096
51.07070.421-0.20754.1454-3.18464.86690.0081-0.0624-0.04210.4819-0.2357-0.5761-0.22670.65820.26180.25320.0539-0.03440.3442-0.03490.3797-5.4182-14.508218.2333
68.920.33422.59822.7907-3.47265.3451-1.27372.68460.0555-0.17150.38580.26030.19110.38930.93820.5366-0.10520.03221.13310.04942.12383.639-7.4688-1.8032
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 10 through 61 )
2X-RAY DIFFRACTION2chain 'A' and (resid 62 through 162 )
3X-RAY DIFFRACTION3chain 'A' and (resid 163 through 186 )
4X-RAY DIFFRACTION4chain 'A' and (resid 187 through 303 )
5X-RAY DIFFRACTION5chain 'A' and (resid 304 through 358 )
6X-RAY DIFFRACTION6chain 'A' and (resid 359 through 359 )

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