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- PDB-4u8z: Crystal structure of MST3 with a pyrrolopyrimidine inhibitor (PF-... -

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Basic information

Entry
Database: PDB / ID: 4u8z
TitleCrystal structure of MST3 with a pyrrolopyrimidine inhibitor (PF-06447475)
ComponentsSerine/threonine-protein kinase 24Serine/threonine-specific protein kinase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / MST3 / pyrrolopyrimidine / inhibitor / kinase / 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 / cytosol / cytoplasm
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-3FE / : / Serine/threonine-protein kinase 24
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.63 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 5, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 18, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 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_initial_refinement_model / pdbx_struct_conn_angle / pdbx_struct_oper_list / refine_hist / struct_conn / struct_conn_type
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_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.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 / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn_type.id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)33,3153
Polymers32,9551
Non-polymers3602
Water4,720262
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area140 Å2
ΔGint-4 kcal/mol
Surface area13970 Å2
MethodPISA
Unit cell
Length a, b, c (Å)99.110, 59.020, 61.810
Angle α, β, γ (deg.)90.00, 93.76, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-488-

HOH

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Components

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


Mass: 32954.770 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-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mn
#3: Chemical ChemComp-3FE / 3-[4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile


Mass: 305.334 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H15N5O
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 262 / 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: 2.74 Å3/Da / Density % sol: 55.06 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 0.1M Tris-HCl (pH 8.5), 180mM MgCl2, 5mM Manganese (II) 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: Jun 27, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.63→37.4 Å / Num. obs: 42612 / % possible obs: 96.3 % / Redundancy: 3.1 % / Biso Wilson estimate: 29.42 Å2 / Rsym value: 0.03 / Net I/σ(I): 16.4

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Processing

SoftwareName: BUSTER / Version: 2.11.2 / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3a7j

3a7j


Resolution: 1.63→37.4 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.9295 / SU R Cruickshank DPI: 0.089 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.091 / SU Rfree Blow DPI: 0.092 / SU Rfree Cruickshank DPI: 0.091
RfactorNum. reflection% reflectionSelection details
Rfree0.2218 2145 5.03 %RANDOM
Rwork0.19 ---
obs0.1916 42607 95.65 %-
Displacement parametersBiso mean: 38.48 Å2
Baniso -1Baniso -2Baniso -3
1-11.9793 Å20 Å23.6764 Å2
2---8.0227 Å20 Å2
3----3.9566 Å2
Refine analyzeLuzzati coordinate error obs: 0.223 Å
Refinement stepCycle: 1 / Resolution: 1.63→37.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2308 0 24 262 2594
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012394HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.073237HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d856SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes63HARMONIC2
X-RAY DIFFRACTIONt_gen_planes352HARMONIC5
X-RAY DIFFRACTIONt_it2394HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.93
X-RAY DIFFRACTIONt_other_torsion17.54
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion310SEMIHARMONIC5
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_contact2952SEMIHARMONIC4
LS refinement shellResolution: 1.63→1.67 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2826 125 5.09 %
Rwork0.245 2329 -
all0.247 2454 -
obs--95.65 %

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