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- PDB-7up5: Crystal structure of C-terminal Domain of MSK1 in complex with co... -

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Basic information

Entry
Database: PDB / ID: 7up5
TitleCrystal structure of C-terminal Domain of MSK1 in complex with covalently bound pyrrolopyrimidine compound 23 (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 / histone H3S10 kinase activity / interleukin-1-mediated signaling pathway / negative regulation of cytokine production / regulation of postsynapse organization / ERK/MAPK targets / Recycling pathway of L1 ...histone H3S28 kinase activity / histone H2AS1 kinase activity / positive regulation of CREB transcription factor activity / CREB phosphorylation / histone H3S10 kinase activity / interleukin-1-mediated signaling pathway / negative regulation of cytokine production / regulation of postsynapse organization / 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 / non-specific serine/threonine protein kinase / intracellular signal transduction / inflammatory response / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / negative regulation of DNA-templated transcription / 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
IODIDE ION / Chem-O1R / Ribosomal protein S6 kinase alpha-5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsYano, J.K. / Edwards, T.E. / 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 1.0Jul 6, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 3, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Apr 3, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)70,2307
Polymers69,3382
Non-polymers8925
Water68538
1
A: Ribosomal protein S6 kinase alpha-5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1784
Polymers34,6691
Non-polymers5093
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Ribosomal protein S6 kinase alpha-5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0513
Polymers34,6691
Non-polymers3832
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)51.480, 90.780, 135.970
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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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.: 2
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-O1R / (2M)-6-chloro-2-(5H-pyrrolo[3,2-d]pyrimidin-5-yl)pyridine-3-carbonitrile


Mass: 255.663 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H6ClN5 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: I
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 38 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.31 Å3/Da / Density % sol: 46.7 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: The protein (10.1 mg/ml) was exchanged into 25 mM HEPES pH 7.5, 150 mM NaCl, 5% glycerol, 1 mM DTT using a GE (GE28-9180-04) spin column according to manufacturer's instructions. The protein ...Details: The protein (10.1 mg/ml) was exchanged into 25 mM HEPES pH 7.5, 150 mM NaCl, 5% glycerol, 1 mM DTT using a GE (GE28-9180-04) spin column according to manufacturer's instructions. The protein was then diluted to 0.5 mg/ml in the same buffer and incubated with 150 micromolar UCB170414/BSI108592 for an hour on ice (~10 fold)and concentrated back down to 5 mg/ml. Crystals were produced by sitting drop vapor diffusion with an equal volume of the protein, Msk1-C terminal domain (PID7059-1, CID101276) and a crystallization buffer containing 12.5% PEG 1000, 12.5% PEG 3350, 12.5% MPD: 30mM of each sodium fluoride/iodide/bromide: 100 mM Na HEPES/MOPS pH 8.5 (tray ID 303042, well B12, Morpheus). Crystals were directly vitrified in in liquid N2. Puck ID QRL9-2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.99999 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 21, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99999 Å / Relative weight: 1
ReflectionResolution: 2.8→50 Å / Num. obs: 16319 / % possible obs: 100 % / Redundancy: 6.495 % / Biso Wilson estimate: 44.306 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.123 / Rrim(I) all: 0.134 / Χ2: 0.973 / Net I/σ(I): 13.83
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rrim(I) all% possible all
2.8-2.876.6910.6163.2411790.8510.668100
2.87-2.956.60.5033.9511420.8970.547100
2.95-3.046.3840.4634.2111410.9150.504100
3.04-3.136.5350.4084.7910720.9240.443100
3.13-3.236.8670.3216.2210760.9550.347100
3.23-3.356.7940.2497.8810230.9710.27100
3.35-3.476.6460.1939.919890.9860.21100
3.47-3.616.4510.16511.039500.9890.18100
3.61-3.786.2720.1313.789150.9930.141100
3.78-3.966.4580.10616.388980.9940.115100
3.96-4.176.760.08420.868450.9960.091100
4.17-4.436.6410.07122.987920.9980.077100
4.43-4.736.3390.06325.127700.9980.06899.9
4.73-5.116.1530.06523.676990.9980.07100
5.11-5.66.6960.08220.396510.9970.08999.8
5.6-6.266.4940.08919.035930.9970.097100
6.26-7.235.9960.07621.375360.9960.084100
7.23-8.856.0660.04829.754570.9990.053100
8.85-12.525.9540.03139.83710.9990.03499.7
12.52-505.1770.02640.922010.02998.2

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
PHENIX1.14-3260refinement
PDB_EXTRACT3.27data extraction
PHENIXphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: in-house model

Resolution: 2.8→48.145 Å / SU ML: 0.37 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 26.72 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2678 1696 10.4 %0
Rwork0.2008 14618 --
obs0.2077 16314 99.95 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 151.41 Å2 / Biso mean: 50.6763 Å2 / Biso min: 12.54 Å2
Refinement stepCycle: final / Resolution: 2.8→48.145 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4220 0 37 38 4295
Biso mean--48.52 35.2 -
Num. residues----561
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork
2.8-2.88240.31921390.25441186
2.8824-2.97540.29891390.23711187
2.9754-3.08170.32291390.2451192
3.0817-3.20510.33941140.23281231
3.2051-3.35090.30671490.23071188
3.3509-3.52750.29161530.20981180
3.5275-3.74850.27561370.19561220
3.7485-4.03780.23661370.17351214
4.0378-4.44390.22881400.16051209
4.4439-5.08630.2181560.15711233
5.0863-6.40580.26711460.22031249
6.4058-48.1450.26941470.21261329
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)
14.2811-0.43351.46264.82741.15440.8782-0.21270.50961.3556-0.08750.0710.758-0.3561-0.8263-0.16780.21350.1106-0.07310.71120.09370.307410.497842.998885.7331
26.7612-0.6788-0.125.9282-1.33584.9845-0.12180.72451.1261-0.2611-0.1530.362-0.5364-0.28310.08290.29410.10210.04550.3530.09170.487316.081742.511684.0248
35.419-0.15770.63593.0872-1.49162.9837-0.11920.16970.0097-0.26320.1198-0.07380.0651-0.11490.16430.17410.07780.02140.31660.03440.225821.238331.82489.2074
48.32871.2622-3.20372.8848-0.50555.3941-0.2929-0.7066-0.25150.02840.14390.04670.0491-0.04850.07680.16750.0270.01890.1901-0.0440.164322.270137.87791.3744
57.03460.4449-5.02054.8472-3.63878.14360.37670.5597-0.23370.1655-0.23790.352-0.4031-0.3223-0.33330.25240.0538-0.03020.27590.01970.269835.99747.160274.0177
63.21820.7691-1.91874.5819-3.49915.5638-0.1907-0.1887-0.01260.03680.01630.0459-0.09480.25870.17610.1791-0.0064-0.00340.2015-0.04210.228939.4438.166683.2959
75.25780.5289-2.98193.6933-1.19735.7528-0.12470.1444-0.5367-0.2180.03970.41160.6337-0.03480.09760.1840.0329-0.02050.24710.01840.360839.085229.770180.525
84.63880.918-1.35184.84571.72921.2295-0.17770.62390.3898-1.0159-0.2450.30411.23420.27570.06111.1492-0.05310.16490.5051-0.15220.3240.630425.286963.4722
94.46720.1549-0.45233.807-0.87246.73490.00830.128-0.0265-0.58810.0106-0.53931.17480.17160.30160.38990.18020.01420.5660.08530.413552.123930.412574.6872
107.6219-1.18376.36294.3014-1.28055.2752-0.47191.11580.4525-0.48020.0174-0.7365-0.55640.6710.71890.2617-0.04170.03480.58140.0490.247550.05343.936972.4093
113.02254.3707-2.26829.4251-0.88374.0792-0.54531.1759-0.29430.98150.22230.87450.9983-2.44580.26241.04070.0791-0.21831.3919-0.4331.226134.368329.156668.2688
128.95491.2384-1.24168.40471.87950.70410.7127-0.2793-0.8090.3694-0.55950.0370.5333-1.0092-0.1550.1892-0.00170.04110.4884-0.04150.3018-4.963251.877544.2075
136.5125-0.0717-0.28047.19670.76136.2109-0.3618-0.2666-0.13170.4567-0.01990.85980.09490.69890.28030.233-0.05910.05640.3233-0.05830.25650.164553.021644.7637
146.89360.1521.71343.04690.07043.0961-0.1256-0.20250.4933-0.0271-0.00570.06-0.32360.35910.07130.23930.01150.01530.3249-0.04750.19075.343861.835836.5979
158.65060.70183.07481.92260.4393.2541-0.2024-0.2106-0.25580.11430.1926-0.0310.187-0.0805-0.14730.21370.04960.00330.2588-0.02120.1615.989255.190536.6289
163.83151.25224.8844.49110.40676.7662-0.2743-0.5419-0.01930.15360.181-0.14590.5161-0.079-0.00220.37290.13180.04470.54610.13080.348620.194452.300856.0763
174.87370.51160.47562.9429-0.70927.0928-0.0899-0.0133-0.15340.21770.1535-0.03070.2899-0.2173-0.04250.13950.0619-0.00430.2625-0.04420.363223.183857.07644.4343
185.59780.41784.24023.27831.04975.2893-0.4604-0.17280.7084-0.06610.0849-0.0005-0.3131-0.15840.23830.20920.07610.00410.4252-0.02550.229123.293766.229343.9948
193.5802-1.7804-0.94444.9722-4.89137.6497-0.2023-1.0891-0.08972.21110.3001-0.9915-1.59810.6596-0.36010.71730.0606-0.06880.514-0.00960.554225.995176.252659.4632
204.8972-0.40780.42976.92033.49862.99170.1287-0.13230.2554-0.18320.4246-1.0127-0.19070.7209-0.28220.21380.00950.02460.4692-0.10160.382436.916466.34949.1829
215.14770.6319-3.94692.38361.89155.9231-0.6756-0.7969-0.15351.01340.2198-0.47711.27510.97520.01330.61730.1469-0.17360.61150.09460.41432.977754.784658.8751
224.5939-4.6794.47586.1354-2.77339.6169-0.2790.3681.0559-0.6480.05552.02620.2301-0.5837-0.5540.45570.0151-0.14610.99990.12151.108919.33997353.345
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 415 through 432 )A415 - 432
2X-RAY DIFFRACTION2chain 'A' and (resid 433 through 450 )A433 - 450
3X-RAY DIFFRACTION3chain 'A' and (resid 451 through 474 )A451 - 474
4X-RAY DIFFRACTION4chain 'A' and (resid 475 through 498 )A475 - 498
5X-RAY DIFFRACTION5chain 'A' and (resid 499 through 517 )A499 - 517
6X-RAY DIFFRACTION6chain 'A' and (resid 518 through 563 )A518 - 563
7X-RAY DIFFRACTION7chain 'A' and (resid 564 through 616 )A564 - 616
8X-RAY DIFFRACTION8chain 'A' and (resid 617 through 641 )A617 - 641
9X-RAY DIFFRACTION9chain 'A' and (resid 642 through 682 )A642 - 682
10X-RAY DIFFRACTION10chain 'A' and (resid 683 through 706 )A683 - 706
11X-RAY DIFFRACTION11chain 'A' and (resid 707 through 722 )A707 - 722
12X-RAY DIFFRACTION12chain 'B' and (resid 415 through 432 )B415 - 432
13X-RAY DIFFRACTION13chain 'B' and (resid 433 through 450 )B433 - 450
14X-RAY DIFFRACTION14chain 'B' and (resid 451 through 474 )B451 - 474
15X-RAY DIFFRACTION15chain 'B' and (resid 475 through 498 )B475 - 498
16X-RAY DIFFRACTION16chain 'B' and (resid 499 through 517 )B499 - 517
17X-RAY DIFFRACTION17chain 'B' and (resid 518 through 563 )B518 - 563
18X-RAY DIFFRACTION18chain 'B' and (resid 564 through 616 )B564 - 616
19X-RAY DIFFRACTION19chain 'B' and (resid 617 through 641 )B617 - 641
20X-RAY DIFFRACTION20chain 'B' and (resid 642 through 686 )B642 - 686
21X-RAY DIFFRACTION21chain 'B' and (resid 687 through 706 )B687 - 706
22X-RAY DIFFRACTION22chain 'B' and (resid 707 through 727 )B707 - 727

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