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- PDB-6yat: Crystal structure of STK4 (MST1) in complex with compound 6 -

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Basic information

Entry
Database: PDB / ID: 6yat
TitleCrystal structure of STK4 (MST1) in complex with compound 6
ComponentsSerine/threonine-protein kinase 4Serine/threonine-specific protein kinase
KeywordsTRANSFERASE / kinase / kinase inhibitor / MST1 / STK4 / hippo pathway / chemical probe / Structural Genomics / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


positive regulation of hepatocyte apoptotic process / cell differentiation involved in embryonic placenta development / regulation of cell differentiation involved in embryonic placenta development / primitive hemopoiesis / neural tube formation / positive regulation of extrinsic apoptotic signaling pathway via death domain receptors / positive regulation of substrate-dependent cell migration, cell attachment to substrate / endocardium development / negative regulation of organ growth / hippo signaling ...positive regulation of hepatocyte apoptotic process / cell differentiation involved in embryonic placenta development / regulation of cell differentiation involved in embryonic placenta development / primitive hemopoiesis / neural tube formation / positive regulation of extrinsic apoptotic signaling pathway via death domain receptors / positive regulation of substrate-dependent cell migration, cell attachment to substrate / endocardium development / negative regulation of organ growth / hippo signaling / Signaling by Hippo / organ growth / branching involved in blood vessel morphogenesis / hepatocyte apoptotic process / regulation of MAPK cascade / extrinsic apoptotic signaling pathway via death domain receptors / canonical Wnt signaling pathway / positive regulation of fat cell differentiation / keratinocyte differentiation / protein serine/threonine kinase activator activity / epithelial cell proliferation / central nervous system development / protein tetramerization / negative regulation of canonical Wnt signaling pathway / cell morphogenesis / protein import into nucleus / negative regulation of epithelial cell proliferation / positive regulation of peptidyl-serine phosphorylation / positive regulation of protein binding / peptidyl-serine phosphorylation / RNA polymerase II-specific DNA-binding transcription factor binding / protein autophosphorylation / protein stabilization / nuclear body / non-specific serine/threonine protein kinase / protein kinase activity / intracellular signal transduction / positive regulation of protein phosphorylation / positive regulation of apoptotic process / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process / magnesium ion binding / signal transduction / protein homodimerization activity / protein-containing complex / nucleoplasm / ATP binding / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Mst1 SARAH domain / C terminal SARAH domain of Mst1 / SARAH domain / SARAH domain profile. / p53-like tetramerisation domain superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site ...Mst1 SARAH domain / C terminal SARAH domain of Mst1 / SARAH domain / SARAH domain profile. / p53-like tetramerisation domain superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-3FX / Chem-OJ5 / Serine/threonine-protein kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.58 Å
AuthorsChaikuad, A. / Bata, N. / Limpert, A.S. / Lambert, L.J. / Bakas, N.A. / Cosford, N.D.P. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: J.Med.Chem. / Year: 2022
Title: Inhibitors of the Hippo Pathway Kinases STK3/MST2 and STK4/MST1 Have Utility for the Treatment of Acute Myeloid Leukemia.
Authors: Bata, N. / Chaikuad, A. / Bakas, N.A. / Limpert, A.S. / Lambert, L.J. / Sheffler, D.J. / Berger, L.M. / Liu, G. / Yuan, C. / Wang, L. / Peng, Y. / Dong, J. / Celeridad, M. / Layng, F. / ...Authors: Bata, N. / Chaikuad, A. / Bakas, N.A. / Limpert, A.S. / Lambert, L.J. / Sheffler, D.J. / Berger, L.M. / Liu, G. / Yuan, C. / Wang, L. / Peng, Y. / Dong, J. / Celeridad, M. / Layng, F. / Knapp, S. / Cosford, N.D.P.
History
DepositionMar 13, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 29, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 8, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Feb 9, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 1.3Jan 24, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Serine/threonine-protein kinase 4
B: Serine/threonine-protein kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,13512
Polymers71,6242
Non-polymers1,51210
Water79344
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2820 Å2
ΔGint-12 kcal/mol
Surface area26450 Å2
Unit cell
Length a, b, c (Å)111.680, 111.680, 171.486
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: 0 / Ens-ID: 1 / Beg auth comp-ID: VAL / Beg label comp-ID: VAL / End auth comp-ID: GLU / End label comp-ID: GLU / Refine code: 0 / Auth seq-ID: 29 - 306 / Label seq-ID: 30 - 307

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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Components

#1: Protein Serine/threonine-protein kinase 4 / Serine/threonine-specific protein kinase / Mammalian STE20-like protein kinase 1 / MST-1 / STE20-like kinase MST1 / Serine/threonine-protein kinase Krs-2


Mass: 35811.902 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: STK4, KRS2, MST1 / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): -R3-pRARE2
References: UniProt: Q13043, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-3FX / (2R)-3-(cyclohexylamino)-2-hydroxypropane-1-sulfonic acid


Mass: 237.316 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H19NO4S
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-OJ5 / 4-[5-(3-chlorophenyl)-7~{H}-pyrrolo[2,3-d]pyrimidin-4-yl]morpholine


Mass: 314.770 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H15ClN4O / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 44 / 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: 3.73 Å3/Da / Density % sol: 67.05 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / pH: 11
Details: 0.6 M ammonium sulfate, 0.1 M lithium sulfate and 0.1 M CAPS, pH 11.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, EMBL c/o DESY / Beamline: P13 (MX1) / Wavelength: 1.0332 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Nov 27, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 2.58→48 Å / Num. obs: 34920 / % possible obs: 100 % / Redundancy: 8 % / CC1/2: 0.998 / Rmerge(I) obs: 0.077 / Rpim(I) all: 0.031 / Rrim(I) all: 0.088 / Net I/σ(I): 15
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2.58-2.728.10.93550130.8240.3741.07100
8.16-47.956.70.04412490.9970.0180.04899.1

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Processing

Software
NameVersionClassification
Aimless0.7.3data scaling
REFMAC5.8.0238refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3com

3com


Resolution: 2.58→48 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.925 / SU B: 20.544 / SU ML: 0.215 / SU R Cruickshank DPI: 0.3235 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.323 / ESU R Free: 0.25
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2585 1727 5 %RANDOM
Rwork0.2252 ---
obs0.2269 33129 99.91 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 194.23 Å2 / Biso mean: 90.644 Å2 / Biso min: 43.61 Å2
Baniso -1Baniso -2Baniso -3
1-0.08 Å2-0 Å2-0 Å2
2--0.08 Å2-0 Å2
3----0.17 Å2
Refinement stepCycle: final / Resolution: 2.58→48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4368 0 101 44 4513
Biso mean--93.67 62.29 -
Num. residues----567
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0134555
X-RAY DIFFRACTIONr_bond_other_d0.0020.0174235
X-RAY DIFFRACTIONr_angle_refined_deg1.0941.6426178
X-RAY DIFFRACTIONr_angle_other_deg1.0691.5839831
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.3945564
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.02723.3200
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.30215760
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.3211520
X-RAY DIFFRACTIONr_chiral_restr0.0380.2619
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.025149
X-RAY DIFFRACTIONr_gen_planes_other0.0070.02871
Refine LS restraints NCS

Ens-ID: 1 / Number: 8092 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.08 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.58→2.647 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.339 114 -
Rwork0.315 2424 -
all-2538 -
obs--100 %
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)
11.45940.12890.17021.5726-0.16690.67640.2360.0243-0.0333-0.0608-0.1972-0.2429-0.1505-0.3375-0.03880.4650.05670.08210.36630.05230.052610.57514.214122.962
20.4763-0.2269-1.53522.24710.5128.76410.2206-0.18690.24650.90910.02180.35630.4683-0.0218-0.24240.9801-0.29560.59790.2585-0.01840.8158.44235.243939.1589
31.34061.7469-0.71432.947-0.31821.27470.1177-0.01010.39970.1916-0.11351.07860.1085-0.1233-0.00410.24680.0079-0.00060.0827-0.05510.872413.510237.156518.3739
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A18 - 308
2X-RAY DIFFRACTION2B29 - 96
3X-RAY DIFFRACTION3B97 - 307

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