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- PDB-5o1s: Dimethyl fumarate is an allosteric covalent inhibitor of the p90 ... -

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Basic information

Entry
Database: PDB / ID: 5o1s
TitleDimethyl fumarate is an allosteric covalent inhibitor of the p90 ribosomal S6 kinases
ComponentsRibosomal protein S6 kinase alpha-3
KeywordsTRANSFERASE / Covalent / Inhibitor / Kinase / allosteric
Function / homology
Function and homology information


RSK activation / CREB phosphorylation / CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling / Gastrin-CREB signalling pathway via PKC and MAPK / Senescence-Associated Secretory Phenotype (SASP) / ribosomal protein S6 kinase activity / ERK/MAPK targets / toll-like receptor signaling pathway / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / response to lipopolysaccharide ...RSK activation / CREB phosphorylation / CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling / Gastrin-CREB signalling pathway via PKC and MAPK / Senescence-Associated Secretory Phenotype (SASP) / ribosomal protein S6 kinase activity / ERK/MAPK targets / toll-like receptor signaling pathway / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / response to lipopolysaccharide / non-specific serine/threonine protein kinase / intracellular signal transduction / cell cycle / phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / nucleolus / protein kinase binding / magnesium ion binding / positive regulation of transcription by RNA polymerase II / nucleoplasm / ATP binding / cytoplasm / cytosol
Similarity search - Function
Ribosomal protein S6 kinase alpha-3, C-terminal catalytic domain / Ribosomal S6 kinase, N-terminal catalytic domain / Ribosomal protein S6 kinase II / Protein kinase, C-terminal / Protein kinase C terminal domain / 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 ...Ribosomal protein S6 kinase alpha-3, C-terminal catalytic domain / Ribosomal S6 kinase, N-terminal catalytic domain / Ribosomal protein S6 kinase II / Protein kinase, C-terminal / Protein kinase C terminal domain / 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
Dimethyl fumarate / Ribosomal protein S6 kinase alpha-3
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsAndersen, J.L. / Nissen, P.
Funding support Denmark, 1items
OrganizationGrant numberCountry
Novo Nordisk Denmark
CitationJournal: Nat Commun / Year: 2018
Title: Dimethyl fumarate is an allosteric covalent inhibitor of the p90 ribosomal S6 kinases.
Authors: Andersen, J.L. / Gesser, B. / Funder, E.D. / Nielsen, C.J.F. / Gotfred-Rasmussen, H. / Rasmussen, M.K. / Toth, R. / Gothelf, K.V. / Arthur, J.S.C. / Iversen, L. / Nissen, P.
History
DepositionMay 19, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 30, 2018Provider: repository / Type: Initial release
Revision 1.1Oct 3, 2018Group: Data collection / Category: reflns / Item: _reflns.pdbx_Rpim_I_all
Revision 1.2Oct 31, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.3Jan 17, 2024Group: Advisory / Data collection ...Advisory / 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 / pdbx_unobs_or_zero_occ_atoms
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Ribosomal protein S6 kinase alpha-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,5574
Polymers41,2421
Non-polymers3153
Water1,820101
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area130 Å2
ΔGint-12 kcal/mol
Surface area14510 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.951, 46.951, 291.865
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212

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Components

#1: Protein Ribosomal protein S6 kinase alpha-3 / S6K-alpha-3 / 90 kDa ribosomal protein S6 kinase 3 / p90RSK3 / MAP kinase-activated protein kinase ...S6K-alpha-3 / 90 kDa ribosomal protein S6 kinase 3 / p90RSK3 / MAP kinase-activated protein kinase 1b / MAPKAPK-1b / Ribosomal S6 kinase 2 / RSK-2 / pp90RSK2


Mass: 41241.832 Da / Num. of mol.: 1 / Fragment: UNP residues 400-740
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Rps6ka3, Mapkapk1b, Rps6ka-rs1, Rsk2 / Production host: Escherichia coli (E. coli)
References: UniProt: P18654, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#3: Chemical ChemComp-9HB / Dimethyl fumarate


Mass: 146.141 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H10O4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 101 / 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: 2.4 Å3/Da / Density % sol: 49 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.1 M Bis-Tris pH 6.5 25 % (w/v) polyethylene glycol (PEG) 3350 0.05 M NaF

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.9 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 3, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9 Å / Relative weight: 1
ReflectionResolution: 1.9→47 Å / Num. obs: 27094 / % possible obs: 99.4 % / Redundancy: 8.6 % / Biso Wilson estimate: 42.2 Å2 / CC1/2: 1 / Rpim(I) all: 0.013 / Net I/σ(I): 23.3
Reflection shellResolution: 1.9→2 Å / Rmerge(I) obs: 0.549 / Mean I/σ(I) obs: 2.3 / CC1/2: 0.56 / Rpim(I) all: 0.321 / % possible all: 96.5

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Processing

Software
NameVersionClassification
PHENIX(1.10_2152: ???)refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2QR8

2qr8


Resolution: 1.9→46.355 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 26.12
RfactorNum. reflection% reflection
Rfree0.2414 1349 5 %
Rwork0.2071 --
obs0.2088 26975 99.33 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.9→46.355 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2309 0 21 101 2431
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0172385
X-RAY DIFFRACTIONf_angle_d1.3513218
X-RAY DIFFRACTIONf_dihedral_angle_d11.0121966
X-RAY DIFFRACTIONf_chiral_restr0.083357
X-RAY DIFFRACTIONf_plane_restr0.012409
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.96790.38711220.31292336X-RAY DIFFRACTION94
1.9679-2.04670.29451330.262515X-RAY DIFFRACTION100
2.0467-2.13990.30491340.24322533X-RAY DIFFRACTION100
2.1399-2.25270.29881310.22982496X-RAY DIFFRACTION100
2.2527-2.39380.27311340.22192536X-RAY DIFFRACTION100
2.3938-2.57860.27191340.21122546X-RAY DIFFRACTION100
2.5786-2.83810.24131350.21452564X-RAY DIFFRACTION100
2.8381-3.24870.24371360.22292591X-RAY DIFFRACTION100
3.2487-4.09260.23621400.19982652X-RAY DIFFRACTION100
4.0926-46.36880.2181500.19112857X-RAY DIFFRACTION100
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)
12.02380.64060.76657.4151-1.23242.00590.3273-1.0198-1.1828-0.1055-0.00411.0741.9477-0.0503-0.22720.7662-0.1293-0.14030.68320.15070.8615-41.73386.1847-16.2829
23.85661.3036-1.14281.21440.28932.1769-0.0871-0.6229-0.29580.20940.08940.04340.26160.1545-0.01380.34360.1719-0.02530.52120.07250.4142-23.923319.558-16.1501
32.80310.0817-0.69536.84152.80364.0735-0.14370.33640.004-0.36510.1653-0.1596-0.30680.5331-0.01260.2164-0.0441-0.01260.57330.03120.367-9.838326.6141-29.3571
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 408:433)
2X-RAY DIFFRACTION2(chain A and resid 434:613)
3X-RAY DIFFRACTION3(chain A and resid 614:712)

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