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- PDB-5lck: A Clickable Covalent ERK 1/2 Inhibitor -

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Basic information

Entry
Database: PDB / ID: 5lck
TitleA Clickable Covalent ERK 1/2 Inhibitor
ComponentsMitogen-activated protein kinase 1
KeywordsTRANSFERASE / Erk2 Covalent inhibitor
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 / lung morphogenesis / positive regulation of macrophage chemotaxis / ERBB2-ERBB3 signaling pathway / response to exogenous dsRNA / regulation of cytoskeleton organization / Activation of the AP-1 family of transcription factors / face development / 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 / RHO GTPases Activate NADPH Oxidases / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / Regulation of HSF1-mediated heat shock response / MAP kinase activity / regulation of ossification / RHO GTPases Activate WASPs and WAVEs / mitogen-activated protein kinase / phosphatase binding / 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 telomerase activity / positive regulation of telomere maintenance via telomerase / cellular response to cadmium ion / NPAS4 regulates expression of target genes / ERK1 and ERK2 cascade / cellular response to amino acid starvation / myelination / 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 / Negative regulation of FGFR2 signaling / FCERI mediated MAPK activation / Negative regulation of FGFR4 signaling / FCGR3A-mediated phagocytosis / Negative regulation of FGFR1 signaling / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / B cell receptor signaling pathway / peptidyl-threonine phosphorylation / 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. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain ...Mitogen-activated protein (MAP) kinase, ERK1/2 / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-6TT / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.89 Å
AuthorsO'Reilly, M. / Wright, D.
CitationJournal: Mol Biosyst / Year: 2016
Title: In-gel activity-based protein profiling of a clickable covalent ERK1/2 inhibitor.
Authors: Lebraud, H. / Wright, D.J. / East, C.E. / Holding, F.P. / O'Reilly, M. / Heightman, T.D.
History
DepositionJun 22, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 20, 2016Provider: repository / Type: Initial release
Revision 1.1Aug 31, 2016Group: Database references
Revision 1.2Mar 28, 2018Group: Source and taxonomy / Category: entity_src_gen
Item: _entity_src_gen.pdbx_host_org_ncbi_taxonomy_id / _entity_src_gen.pdbx_host_org_scientific_name / _entity_src_gen.pdbx_host_org_variant

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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)42,4146
Polymers41,5971
Non-polymers8175
Water8,719484
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area750 Å2
ΔGint-53 kcal/mol
Surface area16410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.861, 70.909, 60.417
Angle α, β, γ (deg.)90.00, 109.43, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Mitogen-activated protein kinase 1 / MAPK 1 / ERT1 / Extracellular signal-regulated kinase 2 / ERK-2 / MAP kinase isoform p42 / p42-MAPK ...MAPK 1 / ERT1 / Extracellular signal-regulated kinase 2 / ERK-2 / MAP kinase isoform p42 / p42-MAPK / Mitogen-activated protein kinase 2 / MAPK 2


Mass: 41596.891 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: CYS 129 and CYS 163 have been modified in the crystallisation solution to CME.
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-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-6TT / ~{N}-[2-[[2-[(5-methoxypyridin-3-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]propanamide


Mass: 432.399 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H19F3N6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 484 / Source method: isolated from a natural source / Formula: H2O

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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: 2.44 Å3/Da / Density % sol: 49.6 %
Crystal growTemperature: 293 K / Method: batch mode / pH: 7.2
Details: 2M (NH4)2SO4 32% MPEG 2000 .02M Mercaptoethanol .1M pH=7.2 HEPES/NaOH

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5417 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Sep 24, 2014 / Details: mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5417 Å / Relative weight: 1
ReflectionResolution: 1.89→30.1 Å / Num. obs: 105730 / % possible obs: 96.4 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.4 % / Biso Wilson estimate: 25.16 Å2 / Rmerge(I) obs: 0.085 / Net I/σ(I): 8.7
Reflection shellResolution: 1.89→1.93 Å / Redundancy: 3 % / Rmerge(I) obs: 0.446 / Mean I/σ(I) obs: 2.1 / % possible all: 73.7

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
iMOSFLMdata reduction
SCALAdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.89→28.5 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.934 / Rfactor Rfree error: 0.02 / SU R Cruickshank DPI: 0.142 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.159 / SU Rfree Blow DPI: 0.143 / SU Rfree Cruickshank DPI: 0.136
Details: Refinement cycles using Buster and rebuilds using COOT
RfactorNum. reflection% reflectionSelection details
Rfree0.212 1550 5.16 %RANDOM
Rwork0.164 ---
obs0.166 30041 96.4 %-
Displacement parametersBiso mean: 34.813 Å2
Baniso -1Baniso -2Baniso -3
1-2.1617 Å20 Å21.115 Å2
2---2.6755 Å20 Å2
3---0.5138 Å2
Refine analyzeLuzzati coordinate error obs: 0.21 Å
Refinement stepCycle: LAST / Resolution: 1.89→28.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2822 0 71 484 3377
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0133012HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.054098HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1060SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes80HARMONIC2
X-RAY DIFFRACTIONt_gen_planes440HARMONIC16
X-RAY DIFFRACTIONt_it3000HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion5.98
X-RAY DIFFRACTIONt_other_torsion16.91
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion380SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3956SEMIHARMONIC4
LS refinement shellResolution: 1.89→1.96 Å / Rfactor Rfree error: 0 / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.252 107 4.77 %
Rwork0.221 2137 -
all0.223 2244 -
obs--73.5 %
Refinement TLS params.Method: refined / Origin x: -1.3788 Å / Origin y: 3.3701 Å / Origin z: 38.1333 Å
111213212223313233
T-0.0664 Å20.007 Å2-0.0054 Å2--0.0645 Å2-0.034 Å2---0.0627 Å2
L1.0014 °2-0.2534 °20.3131 °2-0.5684 °2-0.1874 °2--1.1218 °2
S-0.0647 Å °-0.148 Å °0.1022 Å °0.1068 Å °0.0617 Å °-0.0315 Å °-0.0866 Å °-0.045 Å °0.0031 Å °
Refinement TLS groupSelection details: { A|11 - A|365 }

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