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- PDB-4w8e: Structure of MST3 with a pyrrolopyrimidine inhibitor (PF-06645342) -

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Basic information

Entry
Database: PDB / ID: 4w8e
TitleStructure of MST3 with a pyrrolopyrimidine inhibitor (PF-06645342)
ComponentsSerine/threonine-protein kinase 24 36 kDa subunit
Keywordstransferase/transferase inhibitor / MST3 / pyrrolopyrimidine / Kinase / inhibitor / transferase-transferase inhibitor complex
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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site ...Programmed cell death protein 10, dimerisation domain superfamily / : / Programmed cell death protein 10, dimerisation domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-3JB / Serine/threonine-protein kinase 24
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.79 Å
AuthorsJasti, J. / Song, X. / Griffor, M. / Kurumbail, R.G.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Discovery and preclinical profiling of 3-[4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), a highly potent, selective, brain penetrant, and in vivo active LRRK2 kinase inhibitor.
Authors: Henderson, J.L. / Kormos, B.L. / Hayward, M.M. / Coffman, K.J. / Jasti, J. / Kurumbail, R.G. / Wager, T.T. / Verhoest, P.R. / Noell, G.S. / Chen, Y. / Needle, E. / Berger, Z. / Steyn, S.J. / ...Authors: Henderson, J.L. / Kormos, B.L. / Hayward, M.M. / Coffman, K.J. / Jasti, J. / Kurumbail, R.G. / Wager, T.T. / Verhoest, P.R. / Noell, G.S. / Chen, Y. / Needle, E. / Berger, Z. / Steyn, S.J. / Houle, C. / Hirst, W.D. / Galatsis, P.
History
DepositionAug 24, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 18, 2015Provider: repository / Type: Initial release
Revision 1.1Dec 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description / Source and taxonomy
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / entity_src_gen / pdbx_database_status / pdbx_struct_assembly / pdbx_struct_assembly_prop / pdbx_struct_oper_list / refine_hist
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_assembly_prop.type / _pdbx_struct_assembly_prop.value / _pdbx_struct_oper_list.symmetry_operation / _refine_hist.number_atoms_solvent / _refine_hist.number_atoms_total / _refine_hist.pdbx_number_atoms_ligand / _refine_hist.pdbx_number_atoms_nucleic_acid

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Structure visualization

Structure viewerMolecule:
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Assembly

Deposited unit
A: Serine/threonine-protein kinase 24 36 kDa subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,4292
Polymers33,0421
Non-polymers3871
Water3,981221
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14230 Å2
MethodPISA
Unit cell
Length a, b, c (Å)47.530, 56.490, 61.060
Angle α, β, γ (deg.)90.00, 111.41, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Serine/threonine-protein kinase 24 36 kDa subunit / Mammalian STE20-like protein kinase 3 N-terminal / MST-3/N


Mass: 33041.852 Da / Num. of mol.: 1 / Fragment: UNP residues 9-298
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-3JB / 3-{4-[(2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)morpholin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}benzonitrile


Mass: 387.395 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H17N7O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 221 / Source method: isolated from a natural source / Formula: H2O

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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: 46.75 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 0.1M Tris-HCl (pH 8.5), 180mM MgCl2, 5mM Manganese acetate, 10-17% PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Dec 18, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.79→43.44 Å / Num. obs: 27257 / % possible obs: 96.4 % / Redundancy: 3.4 % / Biso Wilson estimate: 33.68 Å2 / Rsym value: 0.023 / Net I/σ(I): 22.1

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Processing

SoftwareName: BUSTER / Version: 2.11.5 / Classification: refinement
RefinementResolution: 1.79→21.61 Å / Cor.coef. Fo:Fc: 0.9606 / Cor.coef. Fo:Fc free: 0.9446 / SU R Cruickshank DPI: 0.124 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.127 / SU Rfree Blow DPI: 0.119 / SU Rfree Cruickshank DPI: 0.119
RfactorNum. reflection% reflectionSelection details
Rfree0.2125 1389 5.1 %RANDOM
Rwork0.1748 ---
obs0.1767 27227 95.45 %-
Displacement parametersBiso mean: 46.26 Å2
Baniso -1Baniso -2Baniso -3
1-6.2298 Å20 Å23.3155 Å2
2---7.1587 Å20 Å2
3---0.9289 Å2
Refine analyzeLuzzati coordinate error obs: 0.228 Å
Refinement stepCycle: 1 / Resolution: 1.79→21.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2314 0 29 221 2564
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012407HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.033256HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d859SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes63HARMONIC2
X-RAY DIFFRACTIONt_gen_planes360HARMONIC5
X-RAY DIFFRACTIONt_it2407HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.07
X-RAY DIFFRACTIONt_other_torsion17.61
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion311SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2970SEMIHARMONIC4
LS refinement shellResolution: 1.79→1.86 Å / Total num. of bins used: 14
RfactorNum. reflection% reflection
Rfree0.2528 133 4.96 %
Rwork0.221 2547 -
all0.2225 2680 -
obs--95.45 %
Refinement TLS params.Method: refined / Origin x: 7.8471 Å / Origin y: 22.5126 Å / Origin z: 12.1249 Å
111213212223313233
T-0.0936 Å2-0.0073 Å2-0.0063 Å2--0.0947 Å20.005 Å2---0.0726 Å2
L1.4772 °2-0.8782 °2-0.6476 °2-1.6507 °20.8661 °2--1.3011 °2
S-0.0188 Å °-0.1178 Å °0.1056 Å °0.181 Å °0.043 Å °-0.0685 Å °-0.0284 Å °0.0373 Å °-0.0242 Å °
Refinement TLS groupSelection details: { A|* }

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