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- PDB-8pt5: ERK2 covelently bound to RU187 cyclohexenone based inhibitor -

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Basic information

Entry
Database: PDB / ID: 8pt5
TitleERK2 covelently bound to RU187 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: 1.95 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)42,6164
Polymers41,7471
Non-polymers8693
Water1,54986
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: surface plasmon resonance
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1180 Å2
ΔGint-4 kcal/mol
Surface area15720 Å2
Unit cell
Length a, b, c (Å)41.442, 76.836, 123.322
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 RU187 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-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
#3: Chemical ChemComp-D5R / ~{O}3-~{tert}-butyl ~{O}1-methyl (1~{S},3~{R})-1-methyl-4-oxidanylidene-cyclohexane-1,3-dicarboxylate


Mass: 270.321 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H22O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 86 / 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: 2.42 Å3/Da / Density % sol: 49.3 % / Description: rhomboid
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: 10% PEG8000, 0.1 M Na-citrate pH 5.5

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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: 1.95→76.84 Å / Num. obs: 29603 / % possible obs: 100 % / Redundancy: 13.4 % / CC1/2: 0.999 / Rmerge(I) obs: 0.13 / Rpim(I) all: 0.037 / Rrim(I) all: 0.135 / Χ2: 0.99 / Net I/σ(I): 12.3 / Num. measured all: 395767
Reflection shellResolution: 1.95→2 Å / % possible obs: 100 % / Redundancy: 13.7 % / Rmerge(I) obs: 3.428 / Num. measured all: 27917 / Num. unique obs: 2039 / CC1/2: 0.567 / Rpim(I) all: 0.959 / Rrim(I) all: 3.561 / Χ2: 0.99 / Net I/σ(I) obs: 0.9

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Processing

Software
NameVersionClassification
PHENIX1.20.1refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.95→61.66 Å / SU ML: 0.26 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 26.81 / Stereochemistry target values: ML
Details: ideal bond length restraints were used for the CYS-RU67 and HIS-Ru187 covalent bond
RfactorNum. reflection% reflection
Rfree0.2354 1999 6.77 %
Rwork0.2039 --
obs0.2061 29520 99.93 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.95→61.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2698 0 56 86 2840
Refine LS restraints
Refine-IDTypeDev ideal target
X-RAY DIFFRACTIONideal bond length restraints were used for the CYS-RU67 covalent bond bond length CYS161-RU671.69
X-RAY DIFFRACTIONbond length HIS125-RU671.5
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.95-20.39421400.36421916X-RAY DIFFRACTION100
2-2.050.35191410.30241941X-RAY DIFFRACTION100
2.05-2.110.32691390.27091917X-RAY DIFFRACTION100
2.11-2.180.25761430.25281973X-RAY DIFFRACTION100
2.18-2.260.28791390.23721921X-RAY DIFFRACTION100
2.26-2.350.3041410.2381927X-RAY DIFFRACTION100
2.35-2.460.28591430.2351971X-RAY DIFFRACTION100
2.46-2.590.27131410.21991940X-RAY DIFFRACTION100
2.59-2.750.25151420.20791960X-RAY DIFFRACTION100
2.75-2.960.26981420.21191963X-RAY DIFFRACTION100
2.96-3.260.26571420.22051957X-RAY DIFFRACTION100
3.26-3.730.20821450.18631999X-RAY DIFFRACTION100
3.73-4.70.19581470.16272012X-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)
12.69142.06470.70082.09281.13543.79620.11030.14290.1244-0.0914-0.30490.5306-0.4927-0.69820.21320.25490.04740.00310.3897-0.03940.3195-21.7604-12.14872.9902
21.0277-0.0321-0.33313.4795-1.4375.2920.0863-0.0994-0.03860.1331-0.0627-0.20040.11080.2411-0.01550.2199-0.0064-0.02130.2837-0.05050.298-13.9749-16.552816.8018
34.29980.0167-2.02991.28050.1335.19020.2144-0.14090.7750.41230.0591-0.0773-0.63270.48-0.22770.4622-0.0859-0.01790.3719-0.01160.3909-14.8131-11.178129.385
41.553-0.76280.28343.26890.90253.3131-0.1669-0.23360.29070.24240.1585-0.3185-0.39920.13880.03120.7505-0.06980.03830.3713-0.06840.3896-18.7597-6.290142.5881
51.1587-0.1001-0.66132.50360.2023.2892-0.0614-0.2737-0.03920.46530.0338-0.23650.20890.65560.03330.45490.0346-0.09160.42790.02910.3161-11.4741-20.525435.8897
63.74370.14772.60747.9881.86365.55960.17240.419-0.0707-0.64350.2702-0.9886-1.1451.0865-0.42090.4349-0.13240.15370.3849-0.05630.4736-5.3689-2.38123.7307
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 223 )
4X-RAY DIFFRACTION4chain 'A' and (resid 224 through 266 )
5X-RAY DIFFRACTION5chain 'A' and (resid 267 through 339 )
6X-RAY DIFFRACTION6chain 'A' and (resid 340 through 358 )

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