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- PDB-5v62: Phospho-ERK2 bound to bivalent inhibitor SBP3 -

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Basic information

Entry
Database: PDB / ID: 5v62
TitlePhospho-ERK2 bound to bivalent inhibitor SBP3
Components
  • Mitogen-activated protein kinase 1
  • Ribosomal protein S6 kinase alpha-1
KeywordsTRANSFERASE/INHIBITOR / kinase / MAPK / phosphorylation / cancer / TRANSFERASE / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


regulation of translation in response to stress / CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling / ribosomal protein S6 kinase activity / CREB phosphorylation / hepatocyte proliferation / positive regulation of hepatic stellate cell activation / phospho-PLA2 pathway / Signaling by MAPK mutants / RAF-independent MAPK1/3 activation / Suppression of apoptosis ...regulation of translation in response to stress / CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling / ribosomal protein S6 kinase activity / CREB phosphorylation / hepatocyte proliferation / positive regulation of hepatic stellate cell activation / phospho-PLA2 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 / ERKs are inactivated / Signaling by MAP2K mutants / Signaling by NODAL / RSK activation / Golgi Cisternae Pericentriolar Stack Reorganization / negative regulation of TOR signaling / positive regulation of macrophage proliferation / Regulation of the apoptosome activity / outer ear morphogenesis / regulation of cellular pH / regulation of Golgi inheritance / Signaling by LTK in cancer / 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 / ERBB2-ERBB3 signaling pathway / lung morphogenesis / response to exogenous dsRNA / Activation of the AP-1 family of transcription factors / ERK/MAPK targets / regulation of cytoskeleton organization / face development / androgen receptor signaling pathway / pseudopodium / RUNX2 regulates osteoblast differentiation / : / positive regulation of telomere capping / Recycling pathway of L1 / MAPK1 (ERK2) activation / Bergmann glial cell differentiation / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / thyroid gland development / negative regulation of cell differentiation / Advanced glycosylation endproduct receptor signaling / steroid hormone receptor signaling pathway / RHO GTPases Activate NADPH Oxidases / MAP kinase activity / regulation of ossification / Regulation of HSF1-mediated heat shock response / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / mitogen-activated protein kinase / RHO GTPases Activate WASPs and WAVEs / phosphatase binding / Signal attenuation / Estrogen-stimulated signaling through PRKCZ / Transcriptional and post-translational regulation of MITF-M expression and activity / progesterone receptor signaling pathway / Schwann cell development / Nuclear events stimulated by ALK signaling in cancer / Growth hormone receptor signaling / lipopolysaccharide-mediated signaling pathway / stress-activated MAPK cascade / positive regulation of telomere maintenance via telomerase / protein serine/threonine/tyrosine kinase activity / phosphotyrosine residue binding / NPAS4 regulates expression of target genes / cellular response to cadmium ion / myelination / ERK1 and ERK2 cascade / cellular response to amino acid starvation / NCAM signaling for neurite out-growth / ESR-mediated signaling / RNA polymerase II CTD heptapeptide repeat kinase activity / : / insulin-like growth factor receptor signaling pathway / thymus development / positive regulation of peptidyl-threonine phosphorylation / Signal transduction by L1 / Regulation of PTEN gene transcription / long-term synaptic potentiation / response to nicotine / peptidyl-threonine phosphorylation / positive regulation of cell differentiation / Negative regulation of FGFR2 signaling / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / Negative regulation of FGFR3 signaling
Similarity search - Function
Ribosomal S6 kinase, N-terminal catalytic domain / Ribosomal protein S6 kinase II / Mitogen-activated protein (MAP) kinase, ERK1/2 / Protein kinase, C-terminal / Protein kinase C terminal domain / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / Extension to Ser/Thr-type protein kinases / : / AGC-kinase, C-terminal ...Ribosomal S6 kinase, N-terminal catalytic domain / Ribosomal protein S6 kinase II / Mitogen-activated protein (MAP) kinase, ERK1/2 / Protein kinase, C-terminal / Protein kinase C terminal domain / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / Extension to Ser/Thr-type protein kinases / : / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / 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
N-(hex-5-yn-1-yl)hexanamide / Chem-FRZ / Mitogen-activated protein kinase 1 / Ribosomal protein S6 kinase alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / molecular replacement / Resolution: 1.9 Å
AuthorsLechtenberg, B.C. / Riedl, S.J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA160457 United States
CitationJournal: ACS Med Chem Lett / Year: 2017
Title: Structure-Guided Strategy for the Development of Potent Bivalent ERK Inhibitors.
Authors: Lechtenberg, B.C. / Mace, P.D. / Sessions, E.H. / Williamson, R. / Stalder, R. / Wallez, Y. / Roth, G.P. / Riedl, S.J. / Pasquale, E.B.
History
DepositionMar 15, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 26, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 13, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Apr 18, 2018Group: Advisory / Data collection / Database references / Category: citation / pdbx_unobs_or_zero_occ_atoms
Item: _citation.journal_abbrev / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Jul 10, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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
I: Ribosomal protein S6 kinase alpha-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,2999
Polymers43,3162
Non-polymers9837
Water4,594255
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3130 Å2
ΔGint-8 kcal/mol
Surface area17360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.327, 77.888, 152.938
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AI

#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: 40918.828 Da / Num. of mol.: 1 / Fragment: UNP residues 10-360
Source method: isolated from a genetically manipulated source
Details: Dual phosphorylated ERK2 / Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK1, ERK2, PRKM1, PRKM2 / Production host: Escherichia coli (E. coli)
References: UniProt: P28482, mitogen-activated protein kinase
#2: Protein/peptide Ribosomal protein S6 kinase alpha-1 / S6K-alpha-1 / 90 kDa ribosomal protein S6 kinase 1 / p90S6K / MAP kinase-activated protein kinase ...S6K-alpha-1 / 90 kDa ribosomal protein S6 kinase 1 / p90S6K / MAP kinase-activated protein kinase 1a / MAPKAPK-1a / Ribosomal S6 kinase 1 / RSK-1


Mass: 2396.858 Da / Num. of mol.: 1 / Fragment: UNP residues 713-729 / Source method: obtained synthetically / Details: Bivalent ERK inhibitor / Source: (synth.) Homo sapiens (human)
References: UniProt: Q15418, non-specific serine/threonine protein kinase

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Non-polymers , 4 types, 262 molecules

#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-FRZ / 5-(2-PHENYLPYRAZOLO[1,5-A]PYRIDIN-3-YL)-1H-PYRAZOLO[3,4-C]PYRIDAZIN-3-AMINE / FR180204


Mass: 327.343 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H13N7
#5: Chemical ChemComp-AKS / N-(hex-5-yn-1-yl)hexanamide


Mass: 195.301 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H21NO
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 255 / Source method: isolated from a natural source / Formula: H2O

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Details

Nonpolymer detailsLigand AKS links FRZ and azido-lysine (AZK) of peptide inhibitor to form bivalent ERK inhibitor SBP3

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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: 2.92 Å3/Da / Density % sol: 57.88 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 0.1 M Tris-Bicine pH 8.5, 0.02 M each of 1,6-Hexanediol, 1-Butanol, 1,2-Propanediol, 2-Propanol, 1,4-Butanediol, 1,3-Propanediol, 20% v/v PEG550MME, 10% w/v PEG20,000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL11-1 / Wavelength: 0.97852 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 11, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97852 Å / Relative weight: 1
ReflectionResolution: 1.9→19.79 Å / Num. obs: 40711 / % possible obs: 99.8 % / Redundancy: 6.5 % / CC1/2: 0.999 / Rmerge(I) obs: 0.051 / Rpim(I) all: 0.022 / Rrim(I) all: 0.056 / Net I/σ(I): 21.4 / Num. measured all: 266416 / Scaling rejects: 0
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsCC1/2Rpim(I) allRrim(I) all% possible all
1.9-1.946.81.1120.6650.4581.20499.8
8.91-19.795.60.01710.0080.01990.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
REFMACrefinement
Aimless0.3.8data scaling
PDB_EXTRACT3.22data extraction
XDSdata reduction
PHASERphasing
Cootmodel building
RefinementResolution: 1.9→19.79 Å / Cor.coef. Fo:Fc: 0.969 / Cor.coef. Fo:Fc free: 0.954 / WRfactor Rfree: 0.1908 / WRfactor Rwork: 0.1623 / FOM work R set: 0.8565 / SU B: 6.338 / SU ML: 0.09 / SU R Cruickshank DPI: 0.1222 / SU Rfree: 0.1169 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.122 / ESU R Free: 0.117 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2033 2030 5 %RANDOM
Rwork0.1709 ---
obs0.1725 38622 99.63 %-
Solvent computationIon probe radii: 0.7 Å / Shrinkage radii: 0.7 Å / VDW probe radii: 1 Å / Solvent model: MASK
Displacement parametersBiso max: 107.89 Å2 / Biso mean: 41.355 Å2 / Biso min: 22.79 Å2
Baniso -1Baniso -2Baniso -3
1--0.75 Å20 Å20 Å2
2--0.8 Å20 Å2
3----0.06 Å2
Refinement stepCycle: final / Resolution: 1.9→19.79 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2990 0 30 255 3275
Biso mean--78.3 47.21 -
Num. residues----367
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0193236
X-RAY DIFFRACTIONr_bond_other_d0.0020.023013
X-RAY DIFFRACTIONr_angle_refined_deg1.6981.9984390
X-RAY DIFFRACTIONr_angle_other_deg0.98137013
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0635388
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.74723.907151
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.01415572
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.4621522
X-RAY DIFFRACTIONr_chiral_restr0.0930.2474
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0213541
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02655
LS refinement shellResolution: 1.9→1.949 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.306 131 -
Rwork0.275 2792 -
all-2923 -
obs--99.73 %
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)
10.86340.2242-0.01390.96060.26921.75570.0396-0.0236-0.04640.19080.0302-0.03830.12950.083-0.06980.05010.0278-0.01030.0438-0.00270.00565.981618.45323.7987
24.2666-0.8045-1.85339.59452.05521.8570.09960.23580.7544-0.2720.2364-0.1917-0.5401-0.021-0.3360.286-0.00250.01670.11270.03230.13447.333436.310714.4722
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A10 - 360
2X-RAY DIFFRACTION2I713 - 726

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