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- PDB-4zzn: Human ERK2 in complex with an inhibitor -

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Basic information

Entry
Database: PDB / ID: 4zzn
TitleHuman ERK2 in complex with an inhibitor
ComponentsMITOGEN-ACTIVATED PROTEIN KINASE 1
KeywordsTRANSFERASE
Function / homology
Function and homology information


phospho-PLA2 pathway / Signaling by MAPK mutants / Suppression of apoptosis / RAF-independent MAPK1/3 activation / Signaling by Activin / Gastrin-CREB signalling pathway via PKC and MAPK / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / cytosine metabolic process / ERKs are inactivated ...phospho-PLA2 pathway / Signaling by MAPK mutants / Suppression of apoptosis / RAF-independent MAPK1/3 activation / Signaling by Activin / Gastrin-CREB signalling pathway via PKC and MAPK / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / cytosine metabolic process / ERKs are inactivated / response to epidermal growth factor / Signaling by MAP2K mutants / Signaling by NODAL / RSK activation / Golgi Cisternae Pericentriolar Stack Reorganization / regulation of cellular pH / positive regulation of macrophage proliferation / outer ear morphogenesis / Regulation of the apoptosome activity / 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 cytoskeleton organization / 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 / face development / Activation of the AP-1 family of transcription factors / androgen receptor signaling pathway / ERK/MAPK targets / Recycling pathway of L1 / RUNX2 regulates osteoblast differentiation / pseudopodium / progesterone receptor signaling pathway / positive regulation of telomere capping / MAPK1 (ERK2) activation / negative regulation of cell differentiation / Bergmann glial cell differentiation / thyroid gland development / Advanced glycosylation endproduct receptor signaling / steroid hormone mediated signaling pathway / RHO GTPases Activate NADPH Oxidases / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / Regulation of HSF1-mediated heat shock response / regulation of ossification / RHO GTPases Activate WASPs and WAVEs / MAP kinase activity / phosphatase binding / mitogen-activated protein kinase / Signal attenuation / Estrogen-stimulated signaling through PRKCZ / Nuclear events stimulated by ALK signaling in cancer / stress-activated MAPK cascade / Schwann cell development / Growth hormone receptor signaling / lipopolysaccharide-mediated signaling pathway / positive regulation of telomerase activity / ERK1 and ERK2 cascade / cellular response to cadmium ion / cellular response to amino acid starvation / positive regulation of telomere maintenance via telomerase / myelination / NPAS4 regulates expression of target genes / 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 / response to nicotine / positive regulation of peptidyl-threonine phosphorylation / Regulation of PTEN gene transcription / Signal transduction by L1 / long-term synaptic potentiation / caveola / 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 / B cell receptor signaling pathway / Spry regulation of FGF signaling / peptidyl-threonine phosphorylation / Signaling by high-kinase activity BRAF mutants / regulation of protein stability / MAP2K and MAPK activation / 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-CQ8 / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.33 Å
AuthorsWard, R.A. / Colclough, N. / Challinor, M. / Debreczeni, J.E. / Eckersley, K. / Fairley, G. / Feron, L. / Flemington, V. / Graham, M.A. / Greenwood, R. ...Ward, R.A. / Colclough, N. / Challinor, M. / Debreczeni, J.E. / Eckersley, K. / Fairley, G. / Feron, L. / Flemington, V. / Graham, M.A. / Greenwood, R. / Hopcroft, P. / Howard, T.D. / James, M. / Jones, C.D. / Jones, C.R. / Renshaw, J. / Roberts, K. / Snow, L. / Tonge, M. / Yeung, K.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Structure-Guided Design of Highly Selective and Potent Covalent Inhibitors of Erk1/2.
Authors: Ward, R.A. / Colclough, N. / Challinor, M. / Debreczeni, J. / Eckersley, K. / Fairley, G. / Feron, L. / Flemington, V. / Graham, M.A. / Greenwood, R. / Hopcroft, P. / Howard, T.D. / James, M. ...Authors: Ward, R.A. / Colclough, N. / Challinor, M. / Debreczeni, J. / Eckersley, K. / Fairley, G. / Feron, L. / Flemington, V. / Graham, M.A. / Greenwood, R. / Hopcroft, P. / Howard, T.D. / James, M. / Jones, C.D. / Jones, C.R. / Renshaw, J. / Roberts, K. / Snow, L. / Tonge, M. / Yeung, K.
History
DepositionApr 10, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 27, 2015Provider: repository / Type: Initial release
Revision 1.1Aug 26, 2015Group: Database references

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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)41,2493
Polymers40,7921
Non-polymers4572
Water6,575365
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.760, 69.700, 59.800
Angle α, β, γ (deg.)90.00, 108.71, 90.00
Int Tables number4
Space group name H-MP1211

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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: 40791.961 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 11-360
Source method: isolated from a genetically manipulated source
Details: MODIFIED CYS 161 A / Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli)
References: UniProt: P28482, mitogen-activated protein kinase
#2: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-CQ8 / 2-[[5-chloranyl-2-(oxan-4-ylamino)pyridin-4-yl]amino]-N-methyl-benzamide


Mass: 360.838 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H21ClN4O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 365 / 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: 2.36 Å3/Da / Density % sol: 47.97 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.979
DetectorType: DECTRIS PILATUS / Detector: PIXEL / Date: Jul 1, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.33→28.57 Å / Num. obs: 61571 / % possible obs: 70.9 % / Observed criterion σ(I): 2 / Redundancy: 3 % / Biso Wilson estimate: 17.2 Å2 / Rmerge(I) obs: 0.03 / Net I/σ(I): 20.6
Reflection shellResolution: 1.33→1.37 Å / Redundancy: 1.3 % / Rmerge(I) obs: 0.42 / Mean I/σ(I) obs: 1.9 / % possible all: 5.8

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
XDSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.33→28.57 Å / Cor.coef. Fo:Fc: 0.9573 / Cor.coef. Fo:Fc free: 0.9416 / SU R Cruickshank DPI: 0.064 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.067 / SU Rfree Blow DPI: 0.07 / SU Rfree Cruickshank DPI: 0.068
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.2023 12960 21.06 %RANDOM
Rwork0.1703 ---
obs0.1747 61548 70.84 %-
Displacement parametersBiso mean: 23.28 Å2
Baniso -1Baniso -2Baniso -3
1-1.9899 Å20 Å20.4857 Å2
2---4.1049 Å20 Å2
3---2.115 Å2
Refine analyzeLuzzati coordinate error obs: 0.175 Å
Refinement stepCycle: LAST / Resolution: 1.33→28.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2748 0 30 365 3143
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0122855HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.063874HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d993SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes70HARMONIC2
X-RAY DIFFRACTIONt_gen_planes405HARMONIC5
X-RAY DIFFRACTIONt_it2855HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.54
X-RAY DIFFRACTIONt_other_torsion17.5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion369SEMIHARMONIC5
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_contact3685SEMIHARMONIC4
LS refinement shellResolution: 1.33→1.36 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2461 69 19.22 %
Rwork0.2084 290 -
all0.2156 359 -
obs--5.66 %
Refinement TLS params.Method: refined / Origin x: -3.9745 Å / Origin y: 8.1885 Å / Origin z: 47.1496 Å
111213212223313233
T-0.1636 Å20.0101 Å20.0043 Å2--0.1693 Å20.0031 Å2---0.1453 Å2
L0.5417 °20.1275 °20.2177 °2-0.1988 °20.0184 °2--0.9459 °2
S-0.0088 Å °0.0455 Å °0.0415 Å °-0.0182 Å °0.017 Å °0.0034 Å °-0.0372 Å °-0.0273 Å °-0.0081 Å °
Refinement TLS groupSelection details: { A|* }

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