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- PDB-8bzj: Human MST3 (STK24) kinase in complex with inhibitor MRLW5 -

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Basic information

Entry
Database: PDB / ID: 8bzj
TitleHuman MST3 (STK24) kinase in complex with inhibitor MRLW5
ComponentsSerine/threonine-protein kinase 24
KeywordsTRANSFERASE / selective kinase inhibitors / structure-based 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-SJX / Serine/threonine-protein kinase 24
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.52 Å
AuthorsBalourdas, D.I. / Rak, M. / Tesch, R. / Knapp, S. / Joerger, A.C. / Structural Genomics Consortium (SGC)
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research Foundation (DFG)JO 1473/1-3 Germany
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
DepositionDec 14, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 18, 2023Provider: repository / Type: Initial release
Revision 2.0May 24, 2023Group: Non-polymer description / Category: chem_comp / Item: _chem_comp.formula
Revision 2.1Jun 19, 2024Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / 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
A: Serine/threonine-protein kinase 24
B: Serine/threonine-protein kinase 24
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,0795
Polymers69,1192
Non-polymers9603
Water1,40578
1
A: Serine/threonine-protein kinase 24
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0092
Polymers34,5601
Non-polymers4491
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Serine/threonine-protein kinase 24
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0713
Polymers34,5601
Non-polymers5112
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)55.049, 57.737, 61.771
Angle α, β, γ (deg.)88.855, 89.175, 62.120
Int Tables number1
Space group name H-MP1
Space group name HallP1
Symmetry operation#1: x,y,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-SJX / 8-(4-azanylbutyl)-6-[2-chloranyl-4-(6-methylpyridin-2-yl)phenyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one


Mass: 448.948 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H25ClN6O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 78 / 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: 2.51 Å3/Da / Density % sol: 51 %
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 inhibitor). Crystallization buffer: 12% PEG 6000, 0.1 M HEPES pH 7.4.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: May 14, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.52→48.66 Å / Num. obs: 22207 / % possible obs: 97.8 % / Redundancy: 3.4 % / Biso Wilson estimate: 55.7502539151 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.063 / Net I/σ(I): 10
Reflection shellResolution: 2.52→2.62 Å / Redundancy: 3.5 % / Mean I/σ(I) obs: 1.6 / Num. unique obs: 2545 / CC1/2: 0.779 / Rrim(I) all: 0.628 / % possible all: 97.8

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Processing

Software
NameVersionClassification
PHENIX1.10.1_2155refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.52→39.05 Å / SU ML: 0.349584613311 / Cross valid method: FREE R-VALUE / σ(F): 2 / Phase error: 27.7716609642
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.250313678016 1038 4.67672899302 %
Rwork0.182073055088 21157 -
obs0.185132147906 22195 97.7322765302 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 57.9240676092 Å2
Refinement stepCycle: LAST / Resolution: 2.52→39.05 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3997 0 68 78 4143
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.008130253237934180
X-RAY DIFFRACTIONf_angle_d0.9615891464075701
X-RAY DIFFRACTIONf_chiral_restr0.05221838075657
X-RAY DIFFRACTIONf_plane_restr0.00630238740664783
X-RAY DIFFRACTIONf_dihedral_angle_d12.6908302682529
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.52-2.65290.3269077859931450.2531872949593034X-RAY DIFFRACTION97.7552275523
2.6529-2.8190.3228305159591150.239688655433049X-RAY DIFFRACTION97.5940777298
2.819-3.03660.3053548994871260.2381460943733063X-RAY DIFFRACTION97.6722817764
3.0366-3.34210.3246359756452620.230052022482891X-RAY DIFFRACTION98.0410447761
3.3421-3.82530.2369293551621590.177287738773010X-RAY DIFFRACTION97.7181621955
3.8253-4.81810.211784871779900.1464810051153075X-RAY DIFFRACTION97.2649047326
4.8181-39.050.1950529015161410.1623364487243035X-RAY DIFFRACTION98.0852378011

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