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- PDB-5v61: Phospho-ERK2 bound to bivalent inhibitor SBP2 -

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Basic information

Entry
Database: PDB / ID: 5v61
TitlePhospho-ERK2 bound to bivalent inhibitor SBP2
Components
  • Mitogen-activated protein kinase 1
  • Ribosomal protein S6 kinase alpha-1,Protein Tat
KeywordsTRANSFERASE/INHIBITOR / kinase / MAPK / phosphorylation / cancer / TRANSFERASE-TRANSFERASE INHIBITOR complex / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


trans-activation response element binding / Interactions of Tat with host cellular proteins / regulation of translation in response to stress / protein serine/threonine phosphatase inhibitor activity / CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling / positive regulation of viral transcription / ribosomal protein S6 kinase activity / CREB phosphorylation / hepatocyte proliferation / positive regulation of hepatic stellate cell activation ...trans-activation response element binding / Interactions of Tat with host cellular proteins / regulation of translation in response to stress / protein serine/threonine phosphatase inhibitor activity / CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling / positive regulation of viral transcription / ribosomal protein S6 kinase activity / CREB phosphorylation / hepatocyte proliferation / positive regulation of hepatic stellate cell activation / modulation by virus of host chromatin organization / symbiont-mediated suppression of host translation initiation / phospho-PLA2 pathway / Signaling by MAPK mutants / evasion of host immune response / RAF-independent MAPK1/3 activation / Suppression of apoptosis / molecular sequestering activity / host cell nucleolus / 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 / actinin binding / positive regulation of macrophage proliferation / negative regulation of TOR signaling / 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 / negative regulation of peptidyl-threonine phosphorylation / 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 / : / positive regulation of telomere capping / Recycling pathway of L1 / MAPK1 (ERK2) activation / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / 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 / Transcriptional and post-translational regulation of MITF-M expression and activity / RHO GTPases Activate NADPH Oxidases / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / Regulation of HSF1-mediated heat shock response / MAP kinase activity / regulation of ossification / Tat-mediated elongation of the HIV-1 transcript / RNA-binding transcription regulator activity / RHO GTPases Activate WASPs and WAVEs / mitogen-activated protein kinase / Formation of HIV-1 elongation complex containing HIV-1 Tat / 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 / protein serine/threonine/tyrosine kinase activity / myelination / NCAM signaling for neurite out-growth / phosphotyrosine residue binding / cellular response to amino acid starvation
Similarity search - Function
Tat domain superfamily / Immunodeficiency virus transactivating regulatory protein (Tat) / Transactivating regulatory protein (Tat) / 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 ...Tat domain superfamily / Immunodeficiency virus transactivating regulatory protein (Tat) / Transactivating regulatory protein (Tat) / 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
Chem-90A / Chem-FRZ / Protein Tat / Mitogen-activated protein kinase 1 / Ribosomal protein S6 kinase alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human)
HIV-1 M:B_HXB2R (virus)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 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: Data collection / Database references / Category: citation
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _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 1.4Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.5Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Mitogen-activated protein kinase 1
I: Ribosomal protein S6 kinase alpha-1,Protein Tat
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,6987
Polymers44,7872
Non-polymers9115
Water1,65792
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3380 Å2
ΔGint-7 kcal/mol
Surface area17260 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.217, 78.328, 152.187
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: 41258.172 Da / Num. of mol.: 1 / Fragment: UNP residues 8-367
Source method: isolated from a genetically manipulated source
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,Protein Tat / 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 / Transactivating regulatory protein


Mass: 3529.271 Da / Num. of mol.: 1
Fragment: UNP Q15418 residues 713-729, UNP P04608 residues 730-738
Source method: obtained synthetically / Details: RSK1 peptide
Source: (synth.) Homo sapiens (human), (synth.) HIV-1 M:B_HXB2R (virus)
References: UniProt: Q15418, UniProt: P04608, non-specific serine/threonine protein kinase

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Non-polymers , 4 types, 97 molecules

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


Mass: 92.094 Da / Num. of mol.: 3 / 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-90A / 2-oxo-6,9,12,15-tetraoxa-3-azaoctadecan-18-oic acid


Mass: 307.340 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H25NO7
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 92 / Source method: isolated from a natural source / Formula: H2O

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Details

Nonpolymer detailsLigand 90A links FRZ and inhibitor RSK1 peptide to form bivalent ERK inhibitor SBP2

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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: 2.91 Å3/Da / Density % sol: 57.69 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.1 M Bis-Tris pH 6.5, 45% v/v polypropylene glycol P400

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1.075 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Apr 14, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.075 Å / Relative weight: 1
ReflectionResolution: 2.2→19.82 Å / Num. obs: 26480 / % possible obs: 99.9 % / Redundancy: 13.6 % / Rmerge(I) obs: 0.093 / Net I/σ(I): 17.9
Reflection shellResolution: 2.2→2.27 Å / Redundancy: 10.9 % / Rmerge(I) obs: 1.569 / % possible all: 100

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Processing

Software
NameClassification
REFMACrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
CrystalCleardata collection
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2ERK

2erk


Resolution: 2.2→19.82 Å / SU B: 12.483 / SU ML: 0.147 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.201 / ESU R Free: 0.17
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.212 1371 5.2 %RANDOM
Rwork0.176 ---
obs0.178 25051 99.8 %-
Displacement parametersBiso mean: 60.12 Å2
Baniso -1Baniso -2Baniso -3
1--1.22 Å20 Å20 Å2
2--0.54 Å20 Å2
3---0.68 Å2
Refinement stepCycle: LAST / Resolution: 2.2→19.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3047 0 18 92 3157
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)
11.1256-0.08730.0881.2293-0.2253.41970.0806-0.0514-0.0695-0.33520.04590.04420.077-0.1945-0.12650.2296-0.01110.00160.01830.01290.0122-6.76218.3-23.878
29.0907-2.78681.186912.2737-4.30143.0032-0.0103-0.8731.5021-0.05130.16350.7719-0.9874-0.3823-0.15320.85450.1163-0.00210.477-0.17320.4053-8.61336.264-14.082
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A10 - 359
2X-RAY DIFFRACTION2I711 - 727

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