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- PDB-8pt1: ERK2 covelently bound to RU76 cyclohexenone based inhibitor -

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Basic information

Entry
Database: PDB / ID: 8pt1
TitleERK2 covelently bound to RU76 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. / Gogl, G.
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)42,5573
Polymers41,7471
Non-polymers8112
Water3,855214
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: surface plasmon resonance
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area920 Å2
ΔGint-4 kcal/mol
Surface area16120 Å2
MethodPISA
Unit cell
Length a, b, c (Å)41.580, 77.150, 123.680
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 RU76 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-E2A / ~{O}1-methyl ~{O}3-(phenylmethyl) (1~{S},3~{R})-1-methyl-4-oxidanylidene-cyclohexane-1,3-dicarboxylate


Mass: 304.338 Da / Num. of mol.: 1 / Source method: obtained synthetically / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 214 / 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: 7.5 / Details: 20% PEG8000, 0.1 M HEPES pH 7.5

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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
RadiationMonochromator: 1 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→48.25 Å / Num. obs: 37729 / % possible obs: 100 % / Redundancy: 12.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.111 / Rrim(I) all: 0.115 / Net I/σ(I): 13.44
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
1.8-1.851.26127130.781.3161
1.85-1.91.08826980.8251.1341
1.9-1.950.85626020.8860.8931
1.95-2.010.67824990.9390.7071
2.01-2.080.51425050.9460.5361
2.08-2.150.41923560.9740.4371
2.15-2.230.34423090.980.3581
2.23-2.320.28522310.9840.2971
2.32-2.430.24721270.9910.2571
2.43-2.550.20120310.9920.211
2.55-2.680.17519410.9940.1821
2.68-2.850.14218630.9950.1481
2.85-3.040.11517450.9970.121
3.04-3.290.0916230.9980.0941
3.29-3.60.06915050.9990.0721
3.6-4.020.05713770.9980.0591
4.02-4.650.0512260.9990.0531
4.65-5.690.05210450.9980.0551
5.69-8.050.0528380.9990.0541

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Processing

Software
NameVersionClassification
PHENIX1.17refinement
XSCALEdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→48.25 Å / SU ML: 0.19 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 22.47 / Stereochemistry target values: ML
Details: ideal bond length restraints were used for the CYS-RU76 covalent bond
RfactorNum. reflection% reflection
Rfree0.2064 1817 4.82 %
Rwork0.1791 --
obs0.1805 37703 99.91 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.8→48.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2823 0 53 214 3090
Refine LS restraintsType: bond length CYS161-RU67 / Dev ideal target: 1.69
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8-1.850.30121130.27272707X-RAY DIFFRACTION100
1.85-1.90.29311400.25372726X-RAY DIFFRACTION100
1.9-1.960.23251310.22262710X-RAY DIFFRACTION100
1.96-2.030.24711290.22022725X-RAY DIFFRACTION100
2.03-2.120.24831310.1992716X-RAY DIFFRACTION100
2.12-2.210.23121400.19312758X-RAY DIFFRACTION100
2.21-2.330.2231450.1852748X-RAY DIFFRACTION100
2.33-2.470.22171410.18032728X-RAY DIFFRACTION100
2.48-2.670.20061310.18082777X-RAY DIFFRACTION100
2.67-2.930.20961410.18592757X-RAY DIFFRACTION100
2.93-3.360.19911630.17532767X-RAY DIFFRACTION100
3.36-4.230.18841600.15252807X-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)
12.39232.33270.87083.45621.88963.0470.16350.02710.0936-0.0225-0.36950.3768-0.2714-0.56010.17550.17510.04240.0010.2994-0.03410.2359-21.9808-12.67493.4297
24.122-2.7587-2.35322.66172.31157.04190.1197-0.3630.24740.24840.2101-0.27-0.63050.5778-0.33120.2706-0.09990.0520.3252-0.06490.3312-9.2113-5.153814.5288
30.6322-0.2708-0.31912.0872-0.87695.20650.0507-0.0474-0.02210.1072-0.0688-0.09110.25690.1850.01540.18270-0.00850.2377-0.03670.2667-15.3015-18.934617.3337
45.809-1.35770.55271.9238-1.40484.07410.0933-0.15490.9290.993-0.2077-0.1762-0.64530.8073-0.0030.4119-0.1461-0.04830.3748-0.03590.3197-8.3886-10.93922.8428
53.11233.90962.95254.78223.60752.8454-0.05580.66571.4811-1.01410.39960.0102-0.9371.3247-0.36841.0247-0.08630.18310.6776-0.02671.2721-18.0884-1.471226.5248
65.0275-1.15370.03492.36081.69745.2236-0.06930.01470.48360.26880.1792-0.1814-0.27190.5703-0.10150.3952-0.0584-0.02650.2947-0.00310.2416-15.1431-12.219433.5622
74.2481-2.1632.47416.59353.99978.583-0.1175-0.12890.3299-0.1048-0.04110.192-0.8384-0.16540.18790.4589-0.0360.06440.26-0.02390.3181-24.7752-9.114138.5895
81.2694-0.89930.92675.75091.48332.4603-0.4051-0.18180.21190.51070.4052-0.1973-0.13170.30110.07270.64130.0083-0.02390.4021-0.0380.3201-17.1591-9.923647.2464
92.6738-0.5746-1.18872.98610.23154.5715-0.0185-0.2704-0.13190.5758-0.0121-0.38610.51850.9580.01370.42350.0927-0.0930.45490.01160.29-8.6304-24.879835.1288
105.3717-5.48184.23015.3945-4.37283.3219-0.06270.0973-0.51170.0713-0.4301-1.1746-0.50311.33120.53440.555-0.1380.16980.8015-0.03630.8234-0.9892-2.336517.9648
112.7383-0.36521.02725.73550.77583.2470.11240.23270.1476-0.52020.3681-0.782-0.86360.7159-0.49090.3354-0.1060.14130.3141-0.04850.3663-5.5318-2.03683.9099
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 11 through 61 )
2X-RAY DIFFRACTION2chain 'A' and (resid 62 through 77 )
3X-RAY DIFFRACTION3chain 'A' and (resid 78 through 160 )
4X-RAY DIFFRACTION4chain 'A' and (resid 162 through 181 )
5X-RAY DIFFRACTION5chain 'A' and (resid 182 through 191 )
6X-RAY DIFFRACTION6chain 'A' and (resid 192 through 223 )
7X-RAY DIFFRACTION7chain 'A' and (resid 224 through 244 )
8X-RAY DIFFRACTION8chain 'A' and (resid 245 through 283 )
9X-RAY DIFFRACTION9chain 'A' and (resid 284 through 326 )
10X-RAY DIFFRACTION10chain 'A' and (resid 327 through 339 )
11X-RAY DIFFRACTION11chain 'A' and (resid 340 through 359 )

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