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- PDB-7up4: Crystal structure of C-terminal Domain of MSK1 in complex with co... -

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Basic information

Entry
Database: PDB / ID: 7up4
TitleCrystal structure of C-terminal Domain of MSK1 in complex with covalently bound pyrrolopyrimidine compound 20 (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
Chem-O1K / Ribosomal protein S6 kinase alpha-5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 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 1.0Jul 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
Revision 1.3Oct 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

Downloads & links

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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)69,8704
Polymers69,3382
Non-polymers5322
Water905
1
A: Ribosomal protein S6 kinase alpha-5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9352
Polymers34,6691
Non-polymers2661
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)34,9352
Polymers34,6691
Non-polymers2661
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)51.440, 91.180, 136.170
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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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-O1K / (5M)-5-(2,5-dichloropyrimidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine


Mass: 266.086 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H5Cl2N5 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 5 / 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: 2.31 Å3/Da / Density % sol: 46.7 %
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 (PID7059-1, CID101276) at 7.6 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 (PID7059-1, CID101276) at 7.6 mg/ml in 25mM HEPES pH 7.5, 150mM NaCl, 5% Glycerol, 5mM BME and a crystallization buffer containing 20mM of each DL-glutamic acid, DL-alanine, glycine, DL-lysine, DL-serine, sodium HEPES / MOPS (acid) pH 7.5, 12.5% (V/V) MPD, 12.5% (w/V) PEG 1000, 12.5% (w/V) PEG 3350 (tray ID 320260, well H8, Molecular Dimensions / Calibre Morpheus screen ). Crystals were direly vitrified in in liquid N2. Puck ID CNL6-3

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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: Apr 8, 2021
RadiationMonochromator: C(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 3→50 Å / Num. obs: 13380 / % possible obs: 99.7 % / Redundancy: 3.999 % / Biso Wilson estimate: 43.356 Å2 / CC1/2: 0.994 / Rmerge(I) obs: 0.109 / Rrim(I) all: 0.126 / Χ2: 0.915 / Net I/σ(I): 11.27
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rrim(I) all% possible all
3-3.084.0940.5752.469710.7810.663100
3.08-3.164.0580.4613.19550.8470.53199.9
3.16-3.254.1420.3334.269100.9060.38299.9
3.25-3.354.0490.2755.059030.9390.318100
3.35-3.464.1060.2086.48640.9640.2499.9
3.46-3.594.0210.1857.18390.9760.214100
3.59-3.724.1010.1459.278280.9770.16899.9
3.72-3.874.0130.1210.527750.9870.13899.5
3.87-4.054.060.09812.537500.990.11499.9
4.05-4.244.0080.08214.757210.9920.095100
4.24-4.473.9840.0716.446900.9950.08199.7
4.47-4.744.0510.06817.576650.9940.078100
4.74-5.073.9290.06916.696210.9940.0899.7
5.07-5.483.9230.07515.765690.9940.087100
5.48-63.9470.0814.475330.9930.09399.6
6-6.713.8970.06816.554940.9940.07899.8
6.71-7.753.8130.05719.124440.9960.067100
7.75-9.493.7360.03825.213790.9980.044100
9.49-13.423.5950.03129.053040.9990.03699.7
13.42-503.1450.0327.161650.9980.03789.2

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
PHENIX4205refinement
PDB_EXTRACT3.27data extraction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: in-house model

Resolution: 3→48.12 Å / SU ML: 0.4435 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 27.2219
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflectionSelection details
Rfree0.2707 1273 9.52 %0
Rwork0.1906 12103 --
obs0.1984 13376 99.71 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 54.11 Å2
Refinement stepCycle: LAST / Resolution: 3→48.12 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4466 0 32 5 4503
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00424596
X-RAY DIFFRACTIONf_angle_d0.6296175
X-RAY DIFFRACTIONf_chiral_restr0.0418675
X-RAY DIFFRACTIONf_plane_restr0.0041777
X-RAY DIFFRACTIONf_dihedral_angle_d13.57261713
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3-3.120.36941370.26931323X-RAY DIFFRACTION99.93
3.12-3.260.36871380.25591326X-RAY DIFFRACTION99.93
3.26-3.430.28641270.23711338X-RAY DIFFRACTION99.93
3.43-3.650.33341500.21051317X-RAY DIFFRACTION100
3.65-3.930.28131430.18741317X-RAY DIFFRACTION99.66
3.93-4.330.24111390.16571337X-RAY DIFFRACTION99.86
4.33-4.950.22791450.15081344X-RAY DIFFRACTION99.87
4.95-6.240.25011480.1811362X-RAY DIFFRACTION99.67
6.24-48.120.22761460.17481439X-RAY DIFFRACTION98.63
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)
12.531836330890.07605361539251.797145459193.218173604682.011671246823.497811302370.250577935870.2546231266710.417013349895-0.165519964431-0.172563453360.338972613886-0.427099111381-0.939597479756-0.01620062638080.3926703480880.0902272935758-0.07665107973440.6648171895840.06836846353350.24141879720410.19105467542.984586661785.3091853034
29.520116950071.506006361640.7703081847685.385631457291.82220573132.37382770394-0.1292217617860.3682460102670.925417311535-0.09864427490330.152870033378-0.124861595272-0.144945941106-0.0750912166256-0.05966561570.4420235640780.0540655271011-0.09115796304480.4359960325720.04510903171030.27565922488615.61157242842.371079841483.9490102549
36.528580996971.391863595120.0728184360183.66874383654-0.05051418281430.725190485681-0.403673763421-0.368292749739-0.691468506271-0.3312975203720.447438290402-0.1029279243170.0786757948589-0.1570777606730.0672528308470.3939351635430.0839350008267-0.002279940607830.395739654880.05331391386120.19530508093820.793177160931.30352522788.9571603073
47.412158269191.59698317683-3.376025158631.36650104351-0.4261361117013.18210337020.222247857541-0.2534349064850.09956380823240.0310027000055-0.212124600056-0.05213062755560.00099113522038-0.04567918209070.04380426630820.3460068721780.046080218908-0.06473041231710.395872183313-0.006217644795990.21334553833821.77853415437.675135911491.2713235962
57.629371174622.1486053303-4.762711842561.93667030684-1.934700265367.168604668610.3414176053561.28043303616-0.03524466956190.245954341094-0.05319291684740.148884647878-0.687211469117-0.873999141547-0.3887366113560.4694861548630.0297198273223-0.05280505181010.3999187787110.009761975170660.24886724078636.145912361747.890259543473.7982405887
66.4673549241.18160655823-3.023060561792.09148032332-1.793734689314.28050966806-0.122369360527-0.145073150092-0.06135395412340.2661967390740.114247668432-0.08405926479960.00568635808324-0.02400170765110.05795899221680.3748891255510.03757428280470.003787553161150.318053425037-0.03908126747220.27208581261238.868373919438.848134792783.2710761689
76.640772087260.864592940022-3.040724849014.98117554921-2.230066717984.29862162658-0.530602731357-0.15442436231-0.413400113585-0.1166092784460.4871199921230.09382810877441.0788011058-0.2338827652380.03323623189110.4319236462520.0270631060499-0.00155797423450.31616623627-0.02323323583020.31484992391338.749394605929.513028059480.7998758463
83.846857694190.6885813078232.291945240877.304068865385.518609910355.24677335962-0.08928791164350.641568652735-0.812248165203-0.25897800503-0.1428391522230.6379918226261.185163218380.007024934115240.2450588124641.024981468490.04126165501380.173183833520.655608826859-0.03429032126150.53463555000240.394551466424.1602166664.3544933166
95.243461908091.203996263450.4973632659275.804376174361.488953059075.70452010480.2055843148930.351544272292-0.421363246791-0.4157326948450.0285916497633-0.3917004146650.9614681932670.65916130092-0.2182359331370.5078016708070.16116830988-0.05536516794480.540547385690.03162898924760.30053504162852.142595974931.467140240974.6267770246
109.326522833450.03973854301946.310294993974.90458713892-0.3218316473524.41480189201-1.079318248041.037075711260.875917939033-0.2923873111070.199886581345-0.414497601472-1.184034562060.3112974319730.6486506797640.3669452622980.07550381356080.01143443888040.653806272527-0.02692644261050.32017817958848.412932233645.269618976970.6347663266
113.737356035960.4888385762270.2660039824595.48183362430.1840870516553.97537178890.1373965626781.02538703965-0.2174588980820.352175923182-0.942432932586-0.9411898259270.194345175991-1.593336426840.8575657413890.625066526092-0.1753557315310.2208974668391.60446432113-0.6867330554141.9460952380333.710264325429.693401746468.6564834298
122.970209249620.641877955696-0.9565950623844.46078744526-0.9102849779312.45800399644-0.0475703554351-0.1743963146610.05680040588580.0497860900337-0.03357509245530.445825895595-0.205717484498-0.03064380704830.0585616777190.2924907578950.0182666955767-0.009231741639340.532066373113-0.04699489391720.2157982390.6693069643156.671961068741.190657363
134.973070468580.445236073572.264926680450.7916009968510.665321309652.727871148990.00915965924407-0.186481411083-0.0672272627431-0.05970391533650.0184800742793-0.07549630430480.0245204193599-0.189830258022-0.02777776142460.2724937503540.09621276758190.0336523787440.3743287869910.004332627393330.24897426068319.218610047558.717334094644.4535659956
142.51279043897-0.813410168254-1.818048826098.44886423118-0.5952177256511.489979595640.118229287035-0.4186027273710.179675584771.904331347080.171192207958-0.164650556623-0.978936500904-0.14173138073-0.2103118719570.6375357316070.05081141481660.1490006151140.6009542504390.01434933760850.53886519858426.709066333477.066372443459.3055354987
155.74619094461-0.828370222249-2.558100965735.340837240931.17536488643.503797992260.0247122188852-0.4378784294540.02526880847680.2912595821480.0767910827736-0.589582222464-0.1055844032060.483444865408-0.05235524228720.2987730892750.0390674862207-0.05737097192030.512231665756-0.1013858574070.31307488388135.983981258163.471987479752.2147735977
168.78109102214-2.121462424071.058854260027.895226755450.8083832332539.56955764862-0.04971924220961.132589507881.56886210472-0.380849230946-0.2697078497061.552022656-0.933097121605-0.4687166291820.0647468037130.5861101768820.0866792391354-0.1101973693840.9554836672370.1588626039481.1421367719519.12113311973.866177558652.4444699083
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 415 through 432 )AA415 - 4321 - 18
22chain 'A' and (resid 433 through 450 )AA433 - 45019 - 36
33chain 'A' and (resid 451 through 474 )AA451 - 47437 - 60
44chain 'A' and (resid 475 through 498 )AA475 - 49861 - 84
55chain 'A' and (resid 499 through 517 )AA499 - 51785 - 103
66chain 'A' and (resid 518 through 563 )AA518 - 563104 - 145
77chain 'A' and (resid 564 through 616 )AA564 - 616146 - 174
88chain 'A' and (resid 617 through 642 )AA617 - 642175 - 193
99chain 'A' and (resid 643 through 685 )AA643 - 685194 - 236
1010chain 'A' and (resid 686 through 707 )AA686 - 707237 - 258
1111chain 'A' and (resid 708 through 722 )AA708 - 722259 - 273
1212chain 'B' and (resid 415 through 475 )BC415 - 4751 - 61
1313chain 'B' and (resid 476 through 616 )BC476 - 61662 - 175
1414chain 'B' and (resid 617 through 642 )BC617 - 642176 - 201
1515chain 'B' and (resid 643 through 706 )BC643 - 706202 - 265
1616chain 'B' and (resid 707 through 727 )BC707 - 727266 - 286

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