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- PDB-4qtb: Structure of human ERK1 in complex with SCH772984 revealing a nov... -

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Basic information

Entry
Database: PDB / ID: 4qtb
TitleStructure of human ERK1 in complex with SCH772984 revealing a novel inhibitor-induced binding pocket
ComponentsMitogen-activated protein kinase 3
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


positive regulation of xenophagy / xenophagy / 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 / Signaling by MAP2K mutants / Signaling by NODAL ...positive regulation of xenophagy / xenophagy / 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 / Signaling by MAP2K mutants / Signaling by NODAL / ERKs are inactivated / response to epidermal growth factor / RSK activation / positive regulation of cyclase activity / Golgi Cisternae Pericentriolar Stack Reorganization / Regulation of the apoptosome activity / positive regulation of macrophage proliferation / regulation of cellular pH / outer ear morphogenesis / Signaling by LTK in cancer / regulation of Golgi inheritance / interleukin-1-mediated signaling pathway / cartilage development / 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 / phosphorylation / MAPK3 (ERK1) activation / Frs2-mediated activation / ERBB2-ERBB3 signaling pathway / positive regulation of macrophage chemotaxis / Activation of the AP-1 family of transcription factors / regulation of cytoskeleton organization / ERK/MAPK targets / RUNX2 regulates osteoblast differentiation / response to exogenous dsRNA / face development / lung morphogenesis / positive regulation of telomere maintenance / pseudopodium / Bergmann glial cell differentiation / thyroid gland development / Advanced glycosylation endproduct receptor signaling / RHO GTPases Activate NADPH Oxidases / MAP kinase activity / regulation of ossification / signal transduction in response to DNA damage / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / Regulation of HSF1-mediated heat shock response / RHO GTPases Activate WASPs and WAVEs / JUN kinase activity / mitogen-activated protein kinase / BMP signaling pathway / Signal attenuation / phosphatase binding / Schwann cell development / Growth hormone receptor signaling / peptidyl-tyrosine autophosphorylation / stress-activated MAPK cascade / Nuclear events stimulated by ALK signaling in cancer / negative regulation of TORC1 signaling / sensory perception of pain / NPAS4 regulates expression of target genes / phosphotyrosine residue binding / myelination / Transcriptional and post-translational regulation of MITF-M expression and activity / NCAM signaling for neurite out-growth / ERK1 and ERK2 cascade / RNA Polymerase I Promoter Opening / cellular response to amino acid starvation / insulin-like growth factor receptor signaling pathway / lipopolysaccharide-mediated signaling pathway / ESR-mediated signaling / thymus development / Regulation of PTEN gene transcription / Signal transduction by L1 / 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 / modulation of chemical synaptic transmission / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / Oncogene Induced Senescence / caveola / Regulation of actin dynamics for phagocytic cup formation / ISG15 antiviral mechanism / epidermal growth factor receptor signaling pathway / cellular response to mechanical stimulus / Interferon gamma signaling / Signaling by RAF1 mutants / Negative regulation of MAPK pathway / Signaling by moderate kinase activity BRAF mutants
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 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.4 Å
AuthorsChaikuad, A. / Keates, T. / 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

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Assembly

Deposited unit
A: Mitogen-activated protein kinase 3
B: Mitogen-activated protein kinase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)89,50532
Polymers86,5552
Non-polymers2,95030
Water20,0151111
1
A: Mitogen-activated protein kinase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,96019
Polymers43,2781
Non-polymers1,68218
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Mitogen-activated protein kinase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,54513
Polymers43,2781
Non-polymers1,26712
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)61.980, 94.010, 65.360
Angle α, β, γ (deg.)90.00, 91.71, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Mitogen-activated protein kinase 3 / MAP kinase 3 / MAPK 3 / ERT2 / Extracellular signal-regulated kinase 1 / ERK-1 / Insulin-stimulated ...MAP kinase 3 / MAPK 3 / ERT2 / Extracellular signal-regulated kinase 1 / ERK-1 / Insulin-stimulated MAP2 kinase / MAP kinase isoform p44 / p44-MAPK / Microtubule-associated protein 2 kinase / p44-ERK1


Mass: 43277.566 Da / Num. of mol.: 2 / Fragment: kinase domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ERK1, MAPK3, PRKM3 / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21-R3-pRARE2
References: UniProt: P27361, mitogen-activated protein kinase

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Non-polymers , 6 types, 1141 molecules

#2: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 20 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#6: 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.: 2 / Source method: obtained synthetically / Formula: C33H33N9O2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1111 / 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: 2.2 Å3/Da / Density % sol: 44.06 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 33% PEG4000, 0.1 M Tris pH 8.0 and 0.2 M lithium sulphate, VAPOR DIFFUSION, SITTING DROP, temperature 277.15K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.91997 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Oct 5, 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: 0.91997 Å / Relative weight: 1
ReflectionResolution: 1.4→38.15 Å / Num. all: 140419 / Num. obs: 140385 / % possible obs: 95.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 4.1 % / Biso Wilson estimate: 9.8 Å2 / Rmerge(I) obs: 0.089 / Net I/σ(I): 8.8
Reflection shellResolution: 1.4→1.48 Å / Redundancy: 3.9 % / Rmerge(I) obs: 0.618 / Mean I/σ(I) obs: 2.2 / Num. unique all: 19971 / % possible all: 93.3

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Processing

Software
NameVersionClassification
GDAdata collection
PHASERphasing
REFMAC5.7.0032refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 2ZOQ

2zoq


Resolution: 1.4→32.74 Å / Cor.coef. Fo:Fc: 0.976 / Cor.coef. Fo:Fc free: 0.967 / SU B: 1.892 / SU ML: 0.039 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 2 / ESU R: 0.056 / ESU R Free: 0.059 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.17505 7044 5 %RANDOM
Rwork0.14704 ---
obs0.14846 133341 95.55 %-
all-140385 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 16.182 Å2
Baniso -1Baniso -2Baniso -3
1--0.86 Å20 Å2-0.07 Å2
2--1.25 Å20 Å2
3----0.38 Å2
Refine analyzeLuzzati coordinate error obs: 0.143 Å
Refinement stepCycle: LAST / Resolution: 1.4→32.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5692 0 193 1111 6996
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0196273
X-RAY DIFFRACTIONr_bond_other_d0.0010.026104
X-RAY DIFFRACTIONr_angle_refined_deg1.6311.9748500
X-RAY DIFFRACTIONr_angle_other_deg0.789314079
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6955767
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.1423.603297
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.41151126
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.7931548
X-RAY DIFFRACTIONr_chiral_restr0.1080.2921
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.0217316
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021464
X-RAY DIFFRACTIONr_mcbond_it0.9870.8952880
X-RAY DIFFRACTIONr_mcbond_other0.9730.8932879
X-RAY DIFFRACTIONr_mcangle_it1.5551.3393619
X-RAY DIFFRACTIONr_mcangle_other1.5551.3393619
X-RAY DIFFRACTIONr_scbond_it1.8121.1283393
X-RAY DIFFRACTIONr_scbond_other1.8121.1283393
X-RAY DIFFRACTIONr_scangle_other2.781.5984848
X-RAY DIFFRACTIONr_long_range_B_refined6.2529.9198320
X-RAY DIFFRACTIONr_long_range_B_other6.2529.9178318
LS refinement shellResolution: 1.4→1.436 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.291 500 -
Rwork0.266 9557 -
obs--92.8 %
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)
10.1775-0.0042-0.03320.1231-0.04920.2187-0.01110.0028-0.02020.00090.01650.0054-0.0125-0.0028-0.00540.01980.0037-0.00330.0248-0.00450.038431.88346.56557.034
20.33760.37730.81650.75790.53473.36250.0505-0.0275-0.03260.0227-0.0423-0.15080.0679-0.052-0.00810.0226-0.00770.00320.0367-0.00430.075954.23950.04149.561
30.33770.02350.09010.04980.04450.2393-0.01130.00950.0237-0.00690.0105-0.0011-0.00740.00580.00080.0230.00610.00250.01670.00070.039856.59830.85690.64
40.9390.581-1.3860.7833-0.44253.52420.0624-0.09580.02740.0276-0.06370.122-0.05830.10750.00130.0215-0.00690.00510.03440.00790.059734.83227.50781.855
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A24 - 349
2X-RAY DIFFRACTION2A350 - 374
3X-RAY DIFFRACTION3B27 - 349
4X-RAY DIFFRACTION4B350 - 374

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