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- PDB-7up6: Crystal structure of C-terminal domain of MSK1 in complex with in... -

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Basic information

Entry
Database: PDB / ID: 7up6
TitleCrystal structure of C-terminal domain of MSK1 in complex with in covalently bound literature RSK2 inhibitor pyrrolopyrimidine cyanoacrylamide compound 25 (co-crystal)
ComponentsRibosomal protein S6 kinase alpha-5
KeywordsTRANSFERASE / MSK1 / C-TERMINAL DOMAIN / PROTEIN KINASE / PHOSPHORYLATION
Function / homology
Function and homology information


histone H3S28 kinase activity / histone H2AS1 kinase activity / positive regulation of CREB transcription factor activity / CREB phosphorylation / TORC1 signaling / histone H3S10 kinase activity / regulation of postsynapse organization / interleukin-1-mediated signaling pathway / negative regulation of cytokine production / ERK/MAPK targets ...histone H3S28 kinase activity / histone H2AS1 kinase activity / positive regulation of CREB transcription factor activity / CREB phosphorylation / TORC1 signaling / histone H3S10 kinase activity / regulation of postsynapse organization / interleukin-1-mediated signaling pathway / negative regulation of cytokine production / ERK/MAPK targets / Recycling pathway of L1 / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / post-translational protein modification / axon guidance / positive regulation of NF-kappaB transcription factor activity / protein tyrosine kinase activity / protein phosphorylation / non-specific serine/threonine protein kinase / intracellular signal transduction / inflammatory response / protein serine kinase activity / negative regulation of DNA-templated transcription / protein serine/threonine kinase activity / regulation of DNA-templated transcription / magnesium ion binding / positive regulation of transcription by RNA polymerase II / nucleoplasm / ATP binding / nucleus / cytoplasm
Similarity search - Function
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. / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, 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. / 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
Similarity search - Domain/homology
OXAMIC ACID / Chem-SUU / Ribosomal protein S6 kinase alpha-5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsYano, J.K. / Abendroth, J. / Hall, A.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Acs Med.Chem.Lett. / Year: 2022
Title: Discovery and Characterization of a Novel Series of Chloropyrimidines as Covalent Inhibitors of the Kinase MSK1.
Authors: Hall, A. / Abendroth, J. / Bolejack, M.J. / Ceska, T. / Dell'Aiera, S. / Ellis, V. / Fox 3rd, D. / Francois, C. / Muruthi, M.M. / Prevel, C. / Poullennec, K. / Romanov, S. / Valade, A. / ...Authors: Hall, A. / Abendroth, J. / Bolejack, M.J. / Ceska, T. / Dell'Aiera, S. / Ellis, V. / Fox 3rd, D. / Francois, C. / Muruthi, M.M. / Prevel, C. / Poullennec, K. / Romanov, S. / Valade, A. / Vanbellinghen, A. / Yano, J. / Geraerts, M.
History
DepositionApr 14, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 31, 2022Provider: repository / Type: Initial release
Revision 1.1Apr 3, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Ribosomal protein S6 kinase alpha-5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1384
Polymers34,6691
Non-polymers4693
Water88349
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)71.170, 71.170, 144.840
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number169
Space group name H-MP61

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Components

#1: Protein Ribosomal protein S6 kinase alpha-5 / S6K-alpha-5 / 90 kDa ribosomal protein S6 kinase 5 / Nuclear mitogen- and stress-activated protein ...S6K-alpha-5 / 90 kDa ribosomal protein S6 kinase 5 / Nuclear mitogen- and stress-activated protein kinase 1 / RSK-like protein kinase / RSKL


Mass: 34668.809 Da / Num. of mol.: 1 / Fragment: Msk1 CTD 414-738 Delta Pro573-Pro596 GSG
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RPS6KA5, MSK1 / Production host: Escherichia coli (E. coli)
References: UniProt: O75582, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-SUU / (E)-3-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)-2-cyanoacrylamide bound form


Mass: 291.307 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H13N5O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-OXM / OXAMIC ACID


Mass: 89.050 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H3NO3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 49 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 3.06 Å3/Da / Density % sol: 59.8 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: Crystals were produced by sitting drop vapor diffusion with an equal volume of the protein, Msk1-C terminal domain (PID6598-1, CID101276) at 4.91 mg/ml in 25mM HEPES pH 7.5, 150mM NaCl, 5% ...Details: Crystals were produced by sitting drop vapor diffusion with an equal volume of the protein, Msk1-C terminal domain (PID6598-1, CID101276) at 4.91 mg/ml in 25mM HEPES pH 7.5, 150mM NaCl, 5% Glycerol, 5mM BME and a crystallization buffer containing 12.5% PEG 1000, 12.5% PEG 3350, 12.5% MPD: 20mM of each sodium formate, ammonium acetate, trisodium citrate, sodium-potassium tartrate, sodium oxamate: 100 mM MOPS / HEPES-Na pH 7.5 (tray ID 298849, well G8, Morpheus). Crystals were direly vitrified in in liquid N2. Puck ID BOW0-8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97872 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Mar 8, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 2.6→35.59 Å / Num. obs: 12830 / % possible obs: 99.9 % / Redundancy: 7.7 % / Biso Wilson estimate: 51.89 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.084 / Rrim(I) all: 0.09 / Χ2: 1.026 / Net I/σ(I): 17.02 / Num. measured all: 98583
Reflection shellResolution: 2.6→2.67 Å / Redundancy: 7.5 % / Rmerge(I) obs: 0.575 / Mean I/σ(I) obs: 2.82 / Num. measured obs: 1042 / Num. possible: 161 / Num. unique obs: 154 / CC1/2: 0.999 / Rrim(I) all: 0.037 / % possible all: 100

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
PHENIX1.13refinement
PDB_EXTRACT3.27data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: in-house model

Resolution: 2.6→35.59 Å / SU ML: 0.25 / Cross valid method: NONE / σ(F): 1.35 / Phase error: 23.1 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.209 1316 10.32 %0
Rwork0.166 ---
obs0.17 12754 99.7 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 158.58 Å2 / Biso mean: 61.88 Å2 / Biso min: 24.32 Å2
Refinement stepCycle: final / Resolution: 2.6→35.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1935 0 34 49 2018
Biso mean--51.05 55.53 -
Num. residues----257
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0042027
X-RAY DIFFRACTIONf_angle_d0.5932744
X-RAY DIFFRACTIONf_dihedral_angle_d14.7181202
X-RAY DIFFRACTIONf_chiral_restr0.045311
X-RAY DIFFRACTIONf_plane_restr0.004352
LS refinement shellResolution: 2.6→2.7 Å / Rfactor Rfree error: 0 / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.2467 145 -
Rwork0.2035 1272 -
all-1417 -
obs--99 %
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)
15.25112.59280.16566.0483-1.97016.37040.1166-0.1371-0.24910.3646-0.106-0.38890.07180.1287-0.02160.31170.0438-0.02030.24830.02490.3487-19.74246.283647.3375
22.60031.6538-0.42063.7385-1.85776.1432-0.073-0.259-0.08670.1342-0.1648-0.45730.09330.48450.18120.23540.0246-0.00020.27180.00530.2901-16.621512.342339.5092
35.14570.67031.02472.3582-0.37794.4688-0.0050.09830.2080.0826-0.08090.2336-0.0482-0.68170.04590.3320.0548-0.00060.327-0.00950.3091-30.622515.426728.3296
47.01310.50682.32984.9289-0.74387.93520.18030.0828-0.4354-0.26-0.02680.13770.7816-0.3835-0.21260.501-0.0604-0.06420.4477-0.01720.3164-37.70718.011914.9419
59.07361.6780.20367.1945-1.53259.87820.136-0.31120.41310.1396-0.1870.779-0.8596-0.50710.05230.48120.0657-0.09780.5718-0.04420.4382-39.346117.445416.7777
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A0
2X-RAY DIFFRACTION2A0
3X-RAY DIFFRACTION3A0
4X-RAY DIFFRACTION4A0
5X-RAY DIFFRACTION5A0

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