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- PDB-8psr: ERK2 covalently bound to SynthRevD-12-opt artificial peptide -

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Basic information

Entry
Database: PDB / ID: 8psr
TitleERK2 covalently bound to SynthRevD-12-opt artificial peptide
Components
  • Mitogen-activated protein kinase 1
  • SynthRevD-12-opt
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)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsSok, P. / Poti, A. / Gogl, G. / 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

Downloads & links

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Assembly

Deposited unit
A: Mitogen-activated protein kinase 1
B: SynthRevD-12-opt
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,8715
Polymers44,1812
Non-polymers6903
Water5,152286
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3170 Å2
ΔGint-11 kcal/mol
Surface area17740 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.130, 62.130, 214.980
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number170
Space group name H-MP65

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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 / 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: Protein/peptide SynthRevD-12-opt


Mass: 2433.892 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: artificial sequence motif / Source: (synth.) synthetic construct (others)
#3: 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
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 286 / 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: 2.96 Å3/Da / Density % sol: 58.4 % / Description: rhomboid
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: 0.1M Na-citrate pH 5.5, 20% PEG 8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 17, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.85→43.03 Å / Num. obs: 39751 / % possible obs: 99.7 % / Redundancy: 20 % / CC1/2: 0.998 / Rmerge(I) obs: 0.183 / Rrim(I) all: 0.188 / Net I/σ(I): 12.04
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
1.85-1.91.7129280.7831.7541
1.9-1.951.42928710.8341.4671
1.95-2.011.12927690.9041.1591
2.01-2.070.93527110.9190.961
2.07-2.140.75225990.9470.7721
2.14-2.210.63925330.9630.6551
2.21-2.290.52124440.9760.5341
2.29-2.390.44723880.980.4581
2.39-2.490.36422290.9850.3731
2.49-2.620.31121550.9870.3191
2.62-2.760.25520540.9930.2611
2.76-2.930.2119380.9940.2151
2.93-3.130.16818450.9960.1731
3.13-3.380.13216860.9970.1351
3.38-3.70.10515840.9970.1081
3.7-4.140.08914480.9980.0921
4.14-4.780.08112450.9970.0831
4.78-5.850.08210450.9980.0841
5.85-8.270.0848230.9970.0861

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
XSCALEdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.85→43.03 Å / SU ML: 0.25 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 23.66 / Stereochemistry target values: ML
Details: Restrains were used for ABU unnatural aminoacid peptid adducts (1.33) and for the covalent bond to CYS161 (1.75).
RfactorNum. reflection% reflection
Rfree0.2091 2016 5.08 %
Rwork0.1817 --
obs0.1831 39716 99.6 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.85→43.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2984 0 43 286 3313
Refine LS restraintsType: bond length CYS161 SG - ABU C03 / Dev ideal target: 1.75
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.85-1.90.35711580.32152681X-RAY DIFFRACTION99
1.9-1.950.29951340.28272705X-RAY DIFFRACTION99
1.95-20.26841420.24142672X-RAY DIFFRACTION99
2-2.070.24541450.22082677X-RAY DIFFRACTION99
2.07-2.140.2661500.20412666X-RAY DIFFRACTION100
2.14-2.230.26531430.2062657X-RAY DIFFRACTION100
2.23-2.330.21271560.20242676X-RAY DIFFRACTION100
2.33-2.450.24361410.20462723X-RAY DIFFRACTION100
2.45-2.610.19781580.18912677X-RAY DIFFRACTION100
2.61-2.810.18591420.18682704X-RAY DIFFRACTION100
2.81-3.090.20171230.18122718X-RAY DIFFRACTION100
3.09-3.540.19371440.1672694X-RAY DIFFRACTION100
3.54-4.460.18361460.1432717X-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)
11.01080.08110.22014.64610.59731.76990.0938-0.0889-0.4294-0.06510.0144-0.13520.44080.0671-0.10430.2775-0.04720.00230.2310.03490.273573.0096-8.7444-14.1915
21.27260.4372-0.02062.5299-0.37163.32760.0062-0.0783-0.0305-0.1496-0.07470.0635-0.07760.12810.05960.155-0.0416-0.03760.1337-0.00570.169270.5378.7319-16.7696
36.63080.09011.58853.9698-4.00394.4591-0.1325-1.1720.55360.58750.00380.2321-0.82750.02080.12240.3271-0.1056-0.040.2697-0.08630.283568.84818.4915-8.8583
43.80561.51451.48874.58941.0871.79080.1556-0.48340.04520.2524-0.111-0.1545-0.27470.2664-0.02410.4204-0.2161-0.01870.36250.01730.242182.772524.3439-8.4802
59.2134-3.4811.04615.21270.32266.7399-0.0291-1.66510.02250.99240.12410.57360.7656-1.1286-0.08550.8683-0.40030.14460.8661-0.1610.527281.700939.31240.0648
63.02171.15230.79282.63061.15072.0914-0.19850.00810.4182-0.59590.09280.0216-0.83550.45730.11080.6747-0.1996-0.02630.30120.03330.325179.337931.7762-21.4848
73.8307-2.32231.52332.476-3.50817.85510.0622-0.12980.64080.4569-0.1120.5447-0.6826-0.61810.06030.2396-0.06510.07260.3667-0.00850.441857.387.957-4.1486
82.0020.50173.68282.00362.00339.45660.1222-0.5551-1.05380.72050.5933-1.34131.63451.9465-0.71110.64460.0984-0.13380.7019-0.06270.611579.889811.55-34.9689
92.00984.4012-4.85169.7748-4.08034.2526-0.22660.81920.7351-0.15070.2763-0.1934-1.3671-0.3057-0.03550.5047-0.0544-0.14340.30860.04590.372368.831720.6024-39.2947
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 1 through 37 )
2X-RAY DIFFRACTION2chain 'A' and (resid 38 through 162 )
3X-RAY DIFFRACTION3chain 'A' and (resid 163 through 184 )
4X-RAY DIFFRACTION4chain 'A' and (resid 185 through 244 )
5X-RAY DIFFRACTION5chain 'A' and (resid 245 through 266 )
6X-RAY DIFFRACTION6chain 'A' and (resid 267 through 326 )
7X-RAY DIFFRACTION7chain 'A' and (resid 327 through 358 )
8X-RAY DIFFRACTION8chain 'B' and (resid 435 through 442 )
9X-RAY DIFFRACTION9chain 'B' and (resid 443 through 452 )

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