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- PDB-8psw: ERK2 covalently bound to RU67 cyclohexenone based inhibitor -

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Basic information

Entry
Database: PDB / ID: 8psw
TitleERK2 covalently bound to RU67 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 / Signaling by Activin / Gastrin-CREB signalling pathway via PKC and MAPK / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / ERKs are inactivated / cytosine metabolic process ...phospho-PLA2 pathway / Signaling by MAPK mutants / RAF-independent MAPK1/3 activation / Suppression of apoptosis / Signaling by Activin / Gastrin-CREB signalling pathway via PKC and MAPK / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / ERKs are inactivated / cytosine metabolic process / response to epidermal growth factor / Signaling by MAP2K mutants / Signaling by NODAL / RSK activation / Golgi Cisternae Pericentriolar Stack Reorganization / positive regulation of macrophage proliferation / Regulation of the apoptosome activity / outer ear morphogenesis / regulation of cellular pH / regulation of Golgi inheritance / 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 / regulation of stress-activated MAPK cascade / IFNG signaling activates MAPKs / Frs2-mediated activation / positive regulation of macrophage chemotaxis / lung morphogenesis / ERBB2-ERBB3 signaling pathway / response to exogenous dsRNA / regulation of cytoskeleton organization / face development / Activation of the AP-1 family of transcription factors / ERK/MAPK targets / progesterone receptor signaling pathway / androgen receptor signaling pathway / RUNX2 regulates osteoblast differentiation / pseudopodium / Recycling pathway of L1 / MAPK1 (ERK2) activation / Bergmann glial cell differentiation / negative regulation of cell differentiation / positive regulation of telomere capping / thyroid gland development / Advanced glycosylation endproduct receptor signaling / steroid hormone receptor signaling pathway / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / RHO GTPases Activate NADPH Oxidases / Regulation of HSF1-mediated heat shock response / MAP kinase activity / regulation of ossification / RHO GTPases Activate WASPs and WAVEs / phosphatase binding / mitogen-activated protein kinase / Signal attenuation / Estrogen-stimulated signaling through PRKCZ / Nuclear events stimulated by ALK signaling in cancer / Schwann cell development / Growth hormone receptor signaling / stress-activated MAPK cascade / lipopolysaccharide-mediated signaling pathway / : / positive regulation of telomere maintenance via telomerase / cellular response to cadmium ion / NPAS4 regulates expression of target genes / ERK1 and ERK2 cascade / myelination / cellular response to amino acid starvation / NCAM signaling for neurite out-growth / phosphotyrosine residue binding / RNA polymerase II CTD heptapeptide repeat kinase activity / ESR-mediated signaling / insulin-like growth factor receptor signaling pathway / thymus development / positive regulation of peptidyl-threonine phosphorylation / Regulation of PTEN gene transcription / Signal transduction by L1 / caveola / long-term synaptic potentiation / Negative regulation of FGFR3 signaling / Downregulation of SMAD2/3:SMAD4 transcriptional activity / FCERI mediated MAPK activation / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / FCGR3A-mediated phagocytosis / Negative regulation of FGFR1 signaling / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / peptidyl-threonine phosphorylation / B cell receptor signaling pathway / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / response to nicotine / MAP2K and MAPK activation / regulation of protein stability / Oncogene Induced Senescence / mitotic spindle / Regulation of actin dynamics for phagocytic cup formation
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. / Protein kinase domain profile. ...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
AMP PHOSPHORAMIDATE / : / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 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: To Be Published
Title: Targeting a key protein-protein interaction surface on mitogen-activated protein kinases by a Michael acceptor-based cyclic warhead scaffold
Authors: Sok, P. / Poti, A. / Remenyi, A. / Soos, T. / Balint, D.
History
DepositionJul 13, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 24, 2024Provider: repository / Type: Initial release

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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)42,5203
Polymers41,7471
Non-polymers7732
Water1,892105
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: surface plasmon resonance
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area700 Å2
ΔGint-2 kcal/mol
Surface area16310 Å2
Unit cell
Length a, b, c (Å)41.470, 77.390, 127.220
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 RU67 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-AN2 / AMP PHOSPHORAMIDATE


Mass: 426.216 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16N6O9P2
#3: Chemical ChemComp-D2I / ~{O}3-~{tert}-butyl ~{O}1-methyl (1~{R},3~{R})-4-oxidanylidene-1-(phenylmethyl)cyclohexane-1,3-dicarboxylate


Mass: 346.417 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H26O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 105 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 7.5 / Details: 30% PEG1000, 0.1M 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
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→49.14 Å / Num. obs: 28485 / % possible obs: 100 % / Redundancy: 11.8 % / CC1/2: 0.998 / Rmerge(I) obs: 0.149 / Rrim(I) all: 0.155 / Net I/σ(I): 10.49
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
2-2.051.60820580.8711.6841
2.05-2.111.20920140.8711.2661
2.11-2.171.02519690.9111.0731
2.17-2.240.88818980.9040.9291
2.24-2.310.72518930.9510.7581
2.31-2.390.59817560.9670.6241
2.39-2.480.46317510.9790.4831
2.48-2.580.43217010.9760.4511
2.58-2.70.32215630.9890.3361
2.7-2.830.26315550.9880.2741
2.83-2.980.21414860.9930.2241
2.98-3.160.16313850.9940.171
3.16-3.380.14113090.9960.1471
3.38-3.650.11112380.9960.1171
3.65-40.09411360.9960.0981
4-4.470.08610360.9970.091
4.47-5.160.0799430.9980.0831
5.16-6.320.0847790.9980.0871
6.32-8.940.0736340.9970.0771

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Processing

Software
NameVersionClassification
PHENIX1.17.1refinement
XSCALEdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→49.14 Å / SU ML: 0.23 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 23.72 / Stereochemistry target values: ML
Details: ideal bond length restraints were used for the CYS-RU67 covalent bond
RfactorNum. reflection% reflection
Rfree0.2147 1440 5.06 %
Rwork0.1892 --
obs0.1905 28468 99.93 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 53.46 Å2
Refinement stepCycle: LAST / Resolution: 2→49.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2738 0 52 105 2895
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 (%)
2-2.070.3391530.29552630X-RAY DIFFRACTION100
2.07-2.150.2911520.24512648X-RAY DIFFRACTION100
2.15-2.250.24431360.23092655X-RAY DIFFRACTION100
2.25-2.370.29211400.22642668X-RAY DIFFRACTION100
2.37-2.520.2551420.21472673X-RAY DIFFRACTION100
2.52-2.710.22481290.21452704X-RAY DIFFRACTION100
2.71-2.990.27371480.19692698X-RAY DIFFRACTION100
2.99-3.420.1941520.17852698X-RAY DIFFRACTION100
3.42-4.310.16831250.16262766X-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)
11.3472-0.1577-0.27621.72270.95593.75910.04120.07310.03420.149-0.07470.0886-0.0046-0.14180.01510.1522-0.01450.00580.2316-0.01990.2744-17.7255-13.820811.9626
22.1798-0.7177-1.62975.58182.15347.56340.0345-0.16790.33920.4770.1054-0.0578-0.35220.4707-0.09960.3956-0.042-0.03880.2811-0.00590.2919-14.7121-8.621729.465
31.429-1.2651-0.37455.0521.59762.89140.0224-0.2920.09911.17070.0208-0.03840.46230.2774-0.04820.671-0.0061-0.00870.37680.00110.3368-14.5164-13.047440.281
47.35640.2293.55238.8116-0.80559.2237-0.2654-0.05840.1631-0.07770.0816-0.5257-1.05750.74910.17870.2814-0.11810.1220.39580.02270.502-5.4145-1.43087.4534
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 11 through 162 )
2X-RAY DIFFRACTION2chain 'A' and (resid 163 through 223 )
3X-RAY DIFFRACTION3chain 'A' and (resid 224 through 326 )
4X-RAY DIFFRACTION4chain 'A' and (resid 327 through 358 )

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