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- PDB-4qta: Structure of human ERK2 in complex with SCH772984 revealing a nov... -

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Basic information

Entry
Database: PDB / ID: 4qta
TitleStructure of human ERK2 in complex with SCH772984 revealing a novel inhibitor-induced binding pocket
ComponentsMitogen-activated protein kinase 1
KeywordsTransferase/transferase inhibitor / Structural Genomics / Structural Genomics Consortium / SGC / TRANSFERASE / kinase / MAPK / signalling / inhibitor / allosteric / Structural Genomics Consortium (SGC) / Transferase-transferase inhibitor complex
Function / homology
Function and homology information


phospho-PLA2 pathway / interleukin-34-mediated signaling pathway / Signaling by MAPK mutants / RAF-independent MAPK1/3 activation / Suppression of apoptosis / Gastrin-CREB signalling pathway via PKC and MAPK / Signaling by Activin / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / cytosine metabolic process ...phospho-PLA2 pathway / interleukin-34-mediated signaling pathway / Signaling by MAPK mutants / RAF-independent MAPK1/3 activation / Suppression of apoptosis / Gastrin-CREB signalling pathway via PKC and MAPK / Signaling by Activin / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / cytosine metabolic process / response to epidermal growth factor / Signaling by NODAL / ERKs are inactivated / Signaling by MAP2K mutants / RSK activation / Regulation of the apoptosome activity / Golgi Cisternae Pericentriolar Stack Reorganization / positive regulation of macrophage proliferation / regulation of cellular pH / outer ear morphogenesis / Signaling by LTK in cancer / regulation of Golgi inheritance / positive regulation of peptidyl-threonine phosphorylation / 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 / IFNG signaling activates MAPKs / regulation of stress-activated MAPK cascade / Frs2-mediated activation / ERBB2-ERBB3 signaling pathway / Activation of the AP-1 family of transcription factors / regulation of cytoskeleton organization / ERK/MAPK targets / RUNX2 regulates osteoblast differentiation / response to exogenous dsRNA / positive regulation of macrophage chemotaxis / MAPK1 (ERK2) activation / face development / lung morphogenesis / pseudopodium / Bergmann glial cell differentiation / Recycling pathway of L1 / positive regulation of telomere maintenance / thyroid gland development / Advanced glycosylation endproduct receptor signaling / peptidyl-threonine phosphorylation / MAP kinase activity / regulation of ossification / negative regulation of cell differentiation / Regulation of HSF1-mediated heat shock response / RHO GTPases Activate NADPH Oxidases / mitogen-activated protein kinase / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / RHO GTPases Activate WASPs and WAVEs / Signal attenuation / phosphatase binding / Growth hormone receptor signaling / Schwann cell development / Estrogen-stimulated signaling through PRKCZ / stress-activated MAPK cascade / Nuclear events stimulated by ALK signaling in cancer / ERK1 and ERK2 cascade / NPAS4 regulates expression of target genes / phosphotyrosine residue binding / myelination / NCAM signaling for neurite out-growth / RNA polymerase II CTD heptapeptide repeat kinase activity / Transcriptional and post-translational regulation of MITF-M expression and activity / insulin-like growth factor receptor signaling pathway / ESR-mediated signaling / cellular response to amino acid starvation / lipopolysaccharide-mediated signaling pathway / thymus development / Regulation of PTEN gene transcription / Signal transduction by L1 / B cell receptor signaling pathway / response to nicotine / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / Negative regulation of FGFR3 signaling / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / Downregulation of SMAD2/3:SMAD4 transcriptional activity / Negative regulation of FGFR1 signaling / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / positive regulation of cholesterol biosynthetic process / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / Oncogene Induced Senescence / regulation of protein stability / Regulation of actin dynamics for phagocytic cup formation / caveola / epidermal growth factor receptor signaling pathway / long-term synaptic potentiation / Interferon gamma signaling / chemotaxis
Similarity search - Function
Mitogen-activated protein (MAP) kinase, ERK1/2 / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. ...Mitogen-activated protein (MAP) kinase, ERK1/2 / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-38Z / Mitogen-activated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.45 Å
AuthorsChaikuad, A. / Savitsky, P. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: Nat.Chem.Biol. / Year: 2014
Title: A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics.
Authors: Chaikuad, A. / M C Tacconi, E. / Zimmer, J. / Liang, Y. / Gray, N.S. / Tarsounas, M. / Knapp, S.
History
DepositionJul 7, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 23, 2014Provider: repository / Type: Initial release
Revision 1.1Sep 24, 2014Group: Database references
Revision 1.2Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Mitogen-activated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,80812
Polymers41,5321
Non-polymers1,27611
Water7,368409
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.820, 75.540, 103.590
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: 41531.730 Da / Num. of mol.: 1 / Fragment: kinase domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ERK2, MAPK1, PRKM1, PRKM2 / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21-R3-pRARE2
References: UniProt: P28482, mitogen-activated protein kinase
#2: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-38Z / (3R)-1-(2-oxo-2-{4-[4-(pyrimidin-2-yl)phenyl]piperazin-1-yl}ethyl)-N-[3-(pyridin-4-yl)-2H-indazol-5-yl]pyrrolidine-3-carboxamide


Mass: 587.674 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H33N9O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 409 / 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: 2.02 Å3/Da / Density % sol: 39.02 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 30% PEG4000 and 0.2 M ammonium sulphate, pH 7.5, VAPOR DIFFUSION, SITTING DROP, temperature 277.15K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9796 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Dec 2, 2013 / Details: Kirkpatrick Baez bimorph mirror pair
RadiationMonochromator: Si (111) double crystal monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9796 Å / Relative weight: 1
ReflectionResolution: 1.45→33 Å / Num. all: 60441 / Num. obs: 60366 / % possible obs: 99.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 7.9 % / Biso Wilson estimate: 11.9 Å2 / Rmerge(I) obs: 0.09 / Net I/σ(I): 12.5
Reflection shellResolution: 1.45→1.53 Å / Redundancy: 7.5 % / Rmerge(I) obs: 0.71 / Mean I/σ(I) obs: 2.6 / Num. unique all: 8701 / % possible all: 99.7

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Processing

Software
NameVersionClassification
GDAdata collection
PHASERphasing
REFMAC5.8.0049refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 1ERK

1erk
PDB Unreleased entry


Resolution: 1.45→61.04 Å / Cor.coef. Fo:Fc: 0.971 / Cor.coef. Fo:Fc free: 0.96 / SU B: 2.381 / SU ML: 0.047 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 2 / ESU R: 0.064 / ESU R Free: 0.068 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.19147 3046 5 %RANDOM
Rwork0.15839 ---
obs0.16008 57320 99.93 %-
all-60366 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 21.194 Å2
Baniso -1Baniso -2Baniso -3
1--0.69 Å2-0 Å20 Å2
2--0.09 Å20 Å2
3---0.6 Å2
Refine analyzeLuzzati coordinate error obs: 0.163 Å
Refinement stepCycle: LAST / Resolution: 1.45→61.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2715 0 86 409 3210
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0192971
X-RAY DIFFRACTIONr_bond_other_d0.0010.022885
X-RAY DIFFRACTIONr_angle_refined_deg1.6981.9754031
X-RAY DIFFRACTIONr_angle_other_deg0.85336649
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3185363
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.04424.113141
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.9315525
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.0691519
X-RAY DIFFRACTIONr_chiral_restr0.1080.2436
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0213482
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02689
X-RAY DIFFRACTIONr_mcbond_it0.9940.9531368
X-RAY DIFFRACTIONr_mcbond_other0.9930.9521367
X-RAY DIFFRACTIONr_mcangle_it1.5921.4231715
X-RAY DIFFRACTIONr_mcangle_other1.5921.4231715
X-RAY DIFFRACTIONr_scbond_it1.81.2121603
X-RAY DIFFRACTIONr_scbond_other1.81.2121603
X-RAY DIFFRACTIONr_scangle_other2.7451.7212302
X-RAY DIFFRACTIONr_long_range_B_refined6.88710.1293786
X-RAY DIFFRACTIONr_long_range_B_other6.88910.1253784
LS refinement shellResolution: 1.45→1.488 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.267 214 -
Rwork0.255 4169 -
obs--99.34 %
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)
11.0451-0.5799-0.19061.67650.62041.5445-0.001-0.04230.02510.11270.0120.0512-0.102-0.1351-0.0110.04440.01080.00760.02690.0150.021931.80457.51544.425
20.6845-0.23350.94650.6126-0.8951.9849-0.04-0.04420.01660.05930.07680.0327-0.0745-0.1399-0.03680.02650.00570.00580.02340.01050.033230.50561.15228.604
34.3421-3.1225-3.44458.7384.45118.4501-0.237-0.0036-0.84180.12460.05190.01951.2956-0.04380.18510.2743-0.02590.00830.07250.00450.414623.31247.20914.298
42.14690.12210.02450.9886-0.18180.9201-0.00620.2285-0.3169-0.10740.01790.05160.1595-0.0692-0.01170.0566-0.0177-0.01090.0619-0.01260.080420.27656.98310.777
52.43891.34090.15848.54871.78552.61270.0060.1652-0.0141-0.35990.0454-0.3171-0.12160.1447-0.05130.02540.00760.01820.03930.00790.033246.23349.24135.541
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A10 - 66
2X-RAY DIFFRACTION2A67 - 190
3X-RAY DIFFRACTION3A191 - 205
4X-RAY DIFFRACTION4A206 - 334
5X-RAY DIFFRACTION5A335 - 358

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