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- PDB-4zzm: Human ERK2 in complex with an irreversible inhibitor -

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Basic information

Entry
Database: PDB / ID: 4zzm
TitleHuman ERK2 in complex with an irreversible inhibitor
ComponentsMITOGEN-ACTIVATED PROTEIN KINASE 1
KeywordsTRANSFERASE
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 / 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 / negative regulation of cell differentiation / Bergmann glial 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 / 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 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 / 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. / 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-CQ6 / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.89 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)41,2143
Polymers40,7921
Non-polymers4222
Water2,180121
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.880, 70.310, 60.410
Angle α, β, γ (deg.)90.00, 109.12, 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


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-CQ6 / 7-ethylsulfonyl-N-(oxan-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-amine


Mass: 326.414 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H22N4O3S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 121 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsCOMPOUND COVALENTLY BOUND TO PROTEIN 166 CYS A

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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: 2.41 Å3/Da / Density % sol: 48.94 % / 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
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.89→46.18 Å / Num. obs: 30202 / % possible obs: 97.5 % / Observed criterion σ(I): 2 / Redundancy: 3.2 % / Biso Wilson estimate: 31.17 Å2 / Rmerge(I) obs: 0.09 / Net I/σ(I): 8.1
Reflection shellResolution: 1.89→1.94 Å / Redundancy: 3.2 % / Rmerge(I) obs: 0.57 / Mean I/σ(I) obs: 1.9 / % possible all: 96.1

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 1.89→46.18 Å / Cor.coef. Fo:Fc: 0.9451 / Cor.coef. Fo:Fc free: 0.9095 / SU R Cruickshank DPI: 0.154 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.152 / SU Rfree Blow DPI: 0.147 / SU Rfree Cruickshank DPI: 0.149
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.2544 1903 6.3 %RANDOM
Rwork0.2073 ---
obs0.2104 30183 97.32 %-
Displacement parametersBiso mean: 35.19 Å2
Baniso -1Baniso -2Baniso -3
1-2.7015 Å20 Å22.78 Å2
2---4.3448 Å20 Å2
3---1.6433 Å2
Refine analyzeLuzzati coordinate error obs: 0.279 Å
Refinement stepCycle: LAST / Resolution: 1.89→46.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2717 0 27 121 2865
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012812HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.993832HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d950SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes65HARMONIC2
X-RAY DIFFRACTIONt_gen_planes405HARMONIC5
X-RAY DIFFRACTIONt_it2812HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.84
X-RAY DIFFRACTIONt_other_torsion17.76
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion373SEMIHARMONIC5
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_contact3313SEMIHARMONIC4
LS refinement shellResolution: 1.89→1.96 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.4137 206 7.11 %
Rwork0.3331 2693 -
all0.3383 2899 -
obs--95.72 %
Refinement TLS params.Method: refined / Origin x: -4.3088 Å / Origin y: 8.6977 Å / Origin z: 47.38 Å
111213212223313233
T0.0314 Å20.0029 Å20.0788 Å2--0.2071 Å20.0149 Å2---0.1029 Å2
L0.744 °20.2453 °20.1565 °2-0.4498 °20.1753 °2--0.9866 °2
S-0.0302 Å °0.0878 Å °0.0565 Å °-0.063 Å °0.038 Å °0.0116 Å °-0.0869 Å °0.0007 Å °-0.0078 Å °
Refinement TLS groupSelection details: { A|* }

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