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- PDB-8qr4: Crystal structure of ERK2 in complex with a covalently bound macr... -

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Basic information

Entry
Database: PDB / ID: 8qr4
TitleCrystal structure of ERK2 in complex with a covalently bound macrocyclic ligand
ComponentsMitogen-activated protein kinase 1
KeywordsSIGNALING PROTEIN / SERINE/THREONINE-PROTEIN KINASE
Function / homology
Function and homology information


phospho-PLA2 pathway / RAF-independent MAPK1/3 activation / MAPK1 (ERK2) activation / Signaling by NODAL / Frs2-mediated activation / ERK/MAPK targets / ERKs are inactivated / Activation of the AP-1 family of transcription factors / Transcriptional and post-translational regulation of MITF-M expression and activity / Negative feedback regulation of MAPK pathway ...phospho-PLA2 pathway / RAF-independent MAPK1/3 activation / MAPK1 (ERK2) activation / Signaling by NODAL / Frs2-mediated activation / ERK/MAPK targets / ERKs are inactivated / Activation of the AP-1 family of transcription factors / Transcriptional and post-translational regulation of MITF-M expression and activity / Negative feedback regulation of MAPK pathway / Gastrin-CREB signalling pathway via PKC and MAPK / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / IFNG signaling activates MAPKs / Golgi Cisternae Pericentriolar Stack Reorganization / RHO GTPases Activate WASPs and WAVEs / Estrogen-stimulated signaling through PRKCZ / Growth hormone receptor signaling / Spry regulation of FGF signaling / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / Oxidative Stress Induced Senescence / Senescence-Associated Secretory Phenotype (SASP) / Oncogene Induced Senescence / Regulation of actin dynamics for phagocytic cup formation / Downregulation of SMAD2/3:SMAD4 transcriptional activity / Signal attenuation / NCAM signaling for neurite out-growth / Negative regulation of FGFR1 signaling / Negative regulation of FGFR3 signaling / Negative regulation of FGFR4 signaling / Regulation of the apoptosome activity / Signaling by Activin / Negative regulation of FGFR2 signaling / Signal transduction by L1 / RHO GTPases Activate NADPH Oxidases / Negative regulation of MAPK pathway / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Interferon gamma signaling / FCERI mediated MAPK activation / Regulation of HSF1-mediated heat shock response / diadenosine tetraphosphate biosynthetic process / MAP2K and MAPK activation / neural crest cell development / Recycling pathway of L1 / cellular response to toxic substance / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / cytosine metabolic process / mitogen-activated protein kinase kinase kinase binding / cellular response to methionine / response to epidermal growth factor / positive regulation of macrophage proliferation / response to alcohol / regulation of cellular pH / outer ear morphogenesis / regulation of Golgi inheritance / labyrinthine layer blood vessel development / RAF/MAP kinase cascade / Thrombin signalling through proteinase activated receptors (PARs) / ERBB signaling pathway / Neutrophil degranulation / mammary gland epithelial cell proliferation / trachea formation / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / cellular response to insulin-like growth factor stimulus / ERBB2-ERBB3 signaling pathway / positive regulation of macrophage chemotaxis / regulation of cytoskeleton organization / response to exogenous dsRNA / face development / lung morphogenesis / positive regulation of telomere maintenance / response to testosterone / pseudopodium / Bergmann glial cell differentiation / androgen receptor signaling pathway / thyroid gland development / steroid hormone receptor signaling pathway / decidualization / MAP kinase activity / negative regulation of cell differentiation / regulation of ossification / JUN kinase activity / mitogen-activated protein kinase / phosphatase binding / Schwann cell development / progesterone receptor signaling pathway / stress-activated MAPK cascade / estrous cycle / positive regulation of cardiac muscle cell proliferation / cellular response to platelet-derived growth factor stimulus / cellular response to cAMP / sensory perception of pain / dendrite cytoplasm / phosphotyrosine residue binding / myelination / RNA polymerase II CTD heptapeptide repeat kinase activity / peptidyl-threonine phosphorylation / ERK1 and ERK2 cascade / cellular response to epidermal growth factor stimulus
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
: / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.92 Å
AuthorsGelin, M. / Labesse, G.
Funding support France, 1items
OrganizationGrant numberCountry
Agence Nationale de la Recherche (ANR)ANR-20-CE18-0025 France
CitationJournal: To Be Published
Title: Crystal structure of ERK2 in complex with a covalently bound macrocyclic ligand
Authors: Gelin, M. / Labesse, G. / Guichou, J.-F. / Pons, J.-L. / Barluenga, S. / Katickeyan, G. / Winssinger, N.
History
DepositionOct 6, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 16, 2025Provider: 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)42,8724
Polymers42,3121
Non-polymers5613
Water5,999333
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: SAXS, monomer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area360 Å2
ΔGint-23 kcal/mol
Surface area16380 Å2
Unit cell
Length a, b, c (Å)48.620, 70.340, 60.520
Angle α, β, γ (deg.)90.000, 109.780, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Protein Mitogen-activated protein kinase 1


Mass: 42311.668 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Mapk1 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P63086
#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-WN8 / (6~{S},7~{S},12~{S})-12-methyl-6,7,16,18-tetrakis(oxidanyl)-2,13-dioxabicyclo[13.4.0]nonadeca-1(19),15,17-triene-8,14-dione


Mass: 368.378 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H24O8 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 333 / 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: 2.3 Å3/Da / Density % sol: 46.56 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, hanging drop
Details: PEG MME 2000, 0.1M MES pH 6.5, 0.1M ammonium sulfate, 0.02M beta-mercaptoethanol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-1 / Wavelength: 0.979288 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Dec 11, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979288 Å / Relative weight: 1
ReflectionResolution: 1.92→30.92 Å / Num. obs: 29397 / % possible obs: 99.8 % / Redundancy: 3.4 % / Biso Wilson estimate: 20.98 Å2 / CC1/2: 0.959 / Rmerge(I) obs: 0.122 / Rpim(I) all: 0.079 / Rrim(I) all: 0.146 / Χ2: 0.83 / Net I/σ(I): 6.1 / Num. measured all: 99502
Reflection shellResolution: 1.92→1.97 Å / % possible obs: 99.9 % / Redundancy: 3.5 % / Rmerge(I) obs: 0.578 / Num. measured all: 6911 / Num. unique obs: 1999 / CC1/2: 0.494 / Rpim(I) all: 0.374 / Rrim(I) all: 0.692 / Χ2: 0.69 / Net I/σ(I) obs: 2

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
Aimlessdata scaling
MOSFLMdata reduction
PHENIXphasing
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.92→30.92 Å / SU ML: 0.2101 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 24.6989
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2242 1494 5.1 %
Rwork0.1889 27820 -
obs0.1907 29314 99.61 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 29.22 Å2
Refinement stepCycle: LAST / Resolution: 1.92→30.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2777 0 36 333 3146
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00662946
X-RAY DIFFRACTIONf_angle_d0.70433993
X-RAY DIFFRACTIONf_chiral_restr0.0445441
X-RAY DIFFRACTIONf_plane_restr0.0059502
X-RAY DIFFRACTIONf_dihedral_angle_d8.3563410
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.92-1.980.31581430.27092527X-RAY DIFFRACTION99.63
1.98-2.050.24981220.22652517X-RAY DIFFRACTION99.62
2.05-2.140.26471250.21692518X-RAY DIFFRACTION99.17
2.14-2.230.28641340.22232519X-RAY DIFFRACTION99.36
2.23-2.350.27941460.2392491X-RAY DIFFRACTION99.43
2.35-2.50.22271370.19352533X-RAY DIFFRACTION99.78
2.5-2.690.24241370.18372509X-RAY DIFFRACTION99.47
2.69-2.960.20391380.18772517X-RAY DIFFRACTION99.74
2.96-3.390.21411320.17332553X-RAY DIFFRACTION99.93
3.39-4.270.19381290.15622561X-RAY DIFFRACTION99.89
4.27-30.920.19421510.17422575X-RAY DIFFRACTION99.63
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)
11.06665402299-0.120652701095-0.1538432938981.04954823515-0.4584157905343.54412361146-0.05632433909820.1238716554110.218369677379-0.06814322665940.1311657906760.0464006898014-0.599479706577-0.313634154154-0.03931413026930.299507044284-0.0306572231435-0.0553058639820.3385385657450.06763080087330.188731153424-13.414839576211.937429050931.2265630486
21.358943526110.6740041537350.7136945945170.9709207437960.382828980991.44610024684-0.04009635994350.06531755223330.07648138462750.01346425471660.04611144817940.0140423975714-0.0274828476250.0491354751113-0.01345391261170.08976875717160.01275720191120.01466681310490.1056002779670.01553704492050.113243529284-1.932072229698.020021008256.4603036314
30.657078194456-0.01257884087410.05848540024031.8465714944-2.340220781522.98695497588-0.0267822452310.3736101093780.0583715715705-0.435103968845-0.253728620911-0.216823066190.3510214155720.7161804523760.2590207525080.310252433968-0.0492412772385-0.002289213053730.4031279054430.003955855836290.193477278367-3.785455694031.9246460958829.1223907116
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 9 through 98 )9 - 981 - 90
22chain 'A' and (resid 99 through 319 )99 - 31991 - 311
33chain 'A' and (resid 320 through 354 )320 - 354312 - 340

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