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- PDB-8qlr: Human MST3 (STK24) kinase in complex with inhibitor MR24 -

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Basic information

Entry
Database: PDB / ID: 8qlr
TitleHuman MST3 (STK24) kinase in complex with inhibitor MR24
ComponentsSerine/threonine-protein kinase 24
KeywordsTRANSFERASE / Selective kinase inhibitors / structure-guided drug design
Function / homology
Function and homology information


Apoptotic execution phase / regulation of axon regeneration / execution phase of apoptosis / intrinsic apoptotic signaling pathway in response to oxidative stress / positive regulation of axon regeneration / Apoptotic cleavage of cellular proteins / cellular response to starvation / negative regulation of cell migration / cellular response to oxidative stress / protein autophosphorylation ...Apoptotic execution phase / regulation of axon regeneration / execution phase of apoptosis / intrinsic apoptotic signaling pathway in response to oxidative stress / positive regulation of axon regeneration / Apoptotic cleavage of cellular proteins / cellular response to starvation / negative regulation of cell migration / cellular response to oxidative stress / protein autophosphorylation / non-specific serine/threonine protein kinase / protein kinase activity / cadherin binding / Golgi membrane / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / nucleolus / Golgi apparatus / signal transduction / extracellular exosome / nucleoplasm / ATP binding / nucleus / metal ion binding / cytoplasm / cytosol
Similarity search - Function
Programmed cell death protein 10, dimerisation domain superfamily / : / Programmed cell death protein 10, dimerisation domain / 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-VYN / Serine/threonine-protein kinase 24
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsBalourdas, D.I. / Rak, M. / Knapp, S. / Joerger, A.C. / Structural Genomics Consortium (SGC)
Funding support Germany, Canada, 2items
OrganizationGrant numberCountry
German Research Foundation (DFG)JO 1473/1-3 Germany
The Structural Genomics Consortium (SGC) Canada
CitationJournal: J.Med.Chem. / Year: 2024
Title: Development of Selective Pyrido[2,3- d ]pyrimidin-7(8 H )-one-Based Mammalian STE20-Like (MST3/4) Kinase Inhibitors.
Authors: Rak, M. / Menge, A. / Tesch, R. / Berger, L.M. / Balourdas, D.I. / Shevchenko, E. / Kramer, A. / Elson, L. / Berger, B.T. / Abdi, I. / Wahl, L.M. / Poso, A. / Kaiser, A. / Hanke, T. / ...Authors: Rak, M. / Menge, A. / Tesch, R. / Berger, L.M. / Balourdas, D.I. / Shevchenko, E. / Kramer, A. / Elson, L. / Berger, B.T. / Abdi, I. / Wahl, L.M. / Poso, A. / Kaiser, A. / Hanke, T. / Kronenberger, T. / Joerger, A.C. / Muller, S. / Knapp, S.
History
DepositionSep 20, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 8, 2023Provider: repository / Type: Initial release
Revision 1.1Jun 19, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Serine/threonine-protein kinase 24
A: Serine/threonine-protein kinase 24
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,3247
Polymers69,1192
Non-polymers1,2045
Water3,603200
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1520 Å2
ΔGint3 kcal/mol
Surface area23810 Å2
Unit cell
Length a, b, c (Å)55.468, 93.550, 61.792
Angle α, β, γ (deg.)90.00, 92.31, 90.00
Int Tables number4
Space group name H-MP1211
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Protein Serine/threonine-protein kinase 24 / Mammalian STE20-like protein kinase 3 / MST-3 / STE20-like kinase MST3


Mass: 34559.648 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: STK24, MST3, STK3 / Production host: Escherichia coli (E. coli)
References: UniProt: Q9Y6E0, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-VYN / 8-(4-azanylbutyl)-2-[1,3-bis(oxidanyl)propan-2-ylamino]-6-[2-chloranyl-4-(6-methylpyridin-2-yl)phenyl]pyrido[2,3-d]pyrimidin-7-one


Mass: 509.000 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H29ClN6O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 200 / 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: 2.69 Å3/Da / Density % sol: 54.32 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: Protein solution: 11 mg/mL MST3 in 25 mM HEPES pH 7.5, 200 mM NaCl, 0.5 mM TCEP, 5% glycerol) with 1 mM compound MR24. Reservoir solution: 28% PEG 3350, 0.1 M citrate pH 5.6

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 4, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.85→47.7 Å / Num. obs: 52593 / % possible obs: 98 % / Redundancy: 5.9 % / Biso Wilson estimate: 36.367073496 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.037 / Rrim(I) all: 0.04 / Net I/σ(I): 19.5
Reflection shellResolution: 1.85→1.89 Å / Redundancy: 6 % / Rmerge(I) obs: 0.717 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 3231 / CC1/2: 0.89 / Rrim(I) all: 0.784 / % possible all: 98.3

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.85→47.7 Å / SU ML: 0.23 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 28.44 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2169 2628 5 %
Rwork0.1796 --
obs0.1815 52508 97.67 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.85→47.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4044 0 84 200 4328
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0084219
X-RAY DIFFRACTIONf_angle_d0.8715731
X-RAY DIFFRACTIONf_dihedral_angle_d12.6112562
X-RAY DIFFRACTIONf_chiral_restr0.053654
X-RAY DIFFRACTIONf_plane_restr0.006785
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.85-1.88370.30751500.31682601X-RAY DIFFRACTION98
1.8837-1.91990.32741240.27042617X-RAY DIFFRACTION97
1.9199-1.95910.31561400.25352612X-RAY DIFFRACTION98
1.9591-2.00170.27281150.22522633X-RAY DIFFRACTION98
2.0017-2.04830.23571330.20932648X-RAY DIFFRACTION98
2.0483-2.09950.26491370.2072591X-RAY DIFFRACTION98
2.0995-2.15620.23821570.20722615X-RAY DIFFRACTION98
2.1562-2.21970.2541490.19842606X-RAY DIFFRACTION97
2.2197-2.29130.24571240.1922500X-RAY DIFFRACTION93
2.2913-2.37320.25021550.18952614X-RAY DIFFRACTION98
2.3732-2.46820.23781440.19692647X-RAY DIFFRACTION99
2.4682-2.58060.25561420.19362646X-RAY DIFFRACTION99
2.5806-2.71660.25151660.19512612X-RAY DIFFRACTION99
2.7166-2.88680.24761250.19162670X-RAY DIFFRACTION99
2.8868-3.10970.23131380.19562685X-RAY DIFFRACTION99
3.1097-3.42250.2461980.19422565X-RAY DIFFRACTION95
3.4225-3.91760.2021490.16062683X-RAY DIFFRACTION99
3.9176-4.93490.17061480.13852678X-RAY DIFFRACTION99
4.9349-47.70.18371340.17152657X-RAY DIFFRACTION96
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)
11.9213-0.0605-0.28987.2064-1.30815.83950.0735-0.26520.12010.16410.034-0.03940.28440.0183-0.11690.2596-0.01280.00450.3501-0.05680.397934.8113.497252.689
21.27711.1368-0.68093.2547-1.40161.02270.04910.0114-0.0481-0.0687-0.03530.08510.0983-0.0521-0.01150.38770.0779-0.05120.3349-0.03460.335942.934326.716244.5304
32.50880.75430.47111.69490.88813.39430.09940.14840.0093-0.2648-0.0102-0.06840.01180.2576-0.08410.3860.0570.02190.2968-0.00290.297851.132535.850739.8189
47.1974-0.698-0.01627.57780.53685.3711-0.07080.33750.237-0.0850.1035-0.4034-0.7097-0.188-0.05170.5288-0.00670.05190.31820.03850.30919.501240.482212.6094
51.6518-1.72180.44935.4663-2.18253.6599-0.08220.0362-0.07590.17410.14050.165-0.2045-0.0749-0.050.271-0.0380.03030.3102-0.00650.325812.070124.881918.619
62.1685-0.9436-1.69423.70780.95143.7673-0.0346-0.0760.0458-0.01940.1332-0.26060.06510.3161-0.0940.2712-0.0133-0.01450.24820.00950.260226.938113.201516.0496
72.7561-1.4985-1.31485.871.50086.0604-0.1278-0.3286-0.03650.62230.20250.03830.0792-0.0596-0.06790.3504-0.0101-0.00960.32890.05640.31618.456212.189829.0761
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 26 through 103 )
2X-RAY DIFFRACTION2chain 'A' and (resid 104 through 209 )
3X-RAY DIFFRACTION3chain 'A' and (resid 210 through 304 )
4X-RAY DIFFRACTION4chain 'B' and (resid 26 through 73 )
5X-RAY DIFFRACTION5chain 'B' and (resid 74 through 172 )
6X-RAY DIFFRACTION6chain 'B' and (resid 173 through 256 )
7X-RAY DIFFRACTION7chain 'B' and (resid 257 through 304 )

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