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- PDB-9lta: Crystal Structure of Compound SKLB-D18 with MAPK7 (ERK5) -

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Basic information

Entry
Database: PDB / ID: 9lta
TitleCrystal Structure of Compound SKLB-D18 with MAPK7 (ERK5)
ComponentsMitogen-activated protein kinase 7
KeywordsSIGNALING PROTEIN / ERK5 / inhibitor / cancer
Function / homology
Function and homology information


Signalling to ERK5 / negative regulation of response to cytokine stimulus / negative regulation of heterotypic cell-cell adhesion / calcineurin-NFAT signaling cascade / cellular response to laminar fluid shear stress / Gastrin-CREB signalling pathway via PKC and MAPK / ERKs are inactivated / mitogen-activated protein kinase binding / negative regulation of calcineurin-NFAT signaling cascade / ERK/MAPK targets ...Signalling to ERK5 / negative regulation of response to cytokine stimulus / negative regulation of heterotypic cell-cell adhesion / calcineurin-NFAT signaling cascade / cellular response to laminar fluid shear stress / Gastrin-CREB signalling pathway via PKC and MAPK / ERKs are inactivated / mitogen-activated protein kinase binding / negative regulation of calcineurin-NFAT signaling cascade / ERK/MAPK targets / negative regulation of smooth muscle cell apoptotic process / enzyme inhibitor activity / positive regulation of protein metabolic process / RET signaling / MAP kinase activity / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / JUN kinase activity / mitogen-activated protein kinase / regulation of angiogenesis / negative regulation of endothelial cell apoptotic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / cellular response to transforming growth factor beta stimulus / cellular response to growth factor stimulus / PML body / negative regulation of inflammatory response / cellular response to hydrogen peroxide / adenylate cyclase-activating G protein-coupled receptor signaling pathway / MAPK cascade / Senescence-Associated Secretory Phenotype (SASP) / cell differentiation / intracellular signal transduction / protein serine kinase activity / protein serine/threonine kinase activity / signal transduction / positive regulation of transcription by RNA polymerase II / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. ...Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / 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
: / Mitogen-activated protein kinase 7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.33 Å
AuthorsXiao, H. / Sun, Q.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Signal Transduct Target Ther / Year: 2025
Title: A first-in-class selective inhibitor of ERK1/2 and ERK5 overcomes drug resistance with a single-molecule strategy.
Authors: Xiao, H. / Wang, A. / Shuai, W. / Qian, Y. / Wu, C. / Wang, X. / Yang, P. / Sun, Q. / Wang, G. / Ouyang, L. / Sun, Q.
History
DepositionFeb 5, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Apr 2, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
B: Mitogen-activated protein kinase 7
A: Mitogen-activated protein kinase 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)80,4324
Polymers79,4862
Non-polymers9462
Water88349
1
B: Mitogen-activated protein kinase 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,2162
Polymers39,7431
Non-polymers4731
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Mitogen-activated protein kinase 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,2162
Polymers39,7431
Non-polymers4731
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)46.643, 156.917, 49.727
Angle α, β, γ (deg.)90.00, 90.49, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Mitogen-activated protein kinase 7 / MAP kinase 7 / MAPK 7 / Big MAP kinase 1 / BMK-1 / Extracellular signal-regulated kinase 5 / ERK-5


Mass: 39742.766 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK7, BMK1, ERK5, PRKM7 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q13164, mitogen-activated protein kinase
#2: Chemical ChemComp-A1EKR / 4-[5-chloranyl-2-[[3-[(dimethylamino)methyl]phenyl]amino]pyrimidin-4-yl]-~{N}-morpholin-4-yl-thiophene-2-carboxamide


Mass: 472.991 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H25ClN6O2S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 49 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.29 Å3/Da / Density % sol: 46.27 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 0.1M Hepes 7.5, 10% PEG4K, 7% isopropanol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.97861 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 12, 2025
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97861 Å / Relative weight: 1
ReflectionResolution: 2.33→49.73 Å / Num. obs: 29547 / % possible obs: 97.1 % / Redundancy: 6.6 % / CC1/2: 0.996 / Net I/σ(I): 10.7
Reflection shellResolution: 2.33→2.46 Å / Num. unique obs: 4394 / CC1/2: 0.825

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Processing

Software
NameVersionClassification
PHENIX(1.21_5207: ???)refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.33→49.73 Å / SU ML: 0.35 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 34.42 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2916 2028 6.94 %
Rwork0.2493 --
obs0.2523 29206 95.94 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.33→49.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5369 0 64 49 5482
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_dihedral_angle_d16.2572097
X-RAY DIFFRACTIONf_chiral_restr0.049820
X-RAY DIFFRACTIONf_plane_restr0.006972
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.33-2.390.33061380.28321938X-RAY DIFFRACTION97
2.39-2.450.35711540.28942043X-RAY DIFFRACTION99
2.45-2.530.34681360.2951995X-RAY DIFFRACTION100
2.53-2.610.35351630.3042023X-RAY DIFFRACTION100
2.61-2.70.412970.31371386X-RAY DIFFRACTION69
2.7-2.810.38881590.30252000X-RAY DIFFRACTION100
2.81-2.940.34841300.29282006X-RAY DIFFRACTION98
2.94-3.090.37641510.30822025X-RAY DIFFRACTION100
3.09-3.280.34061440.27691992X-RAY DIFFRACTION99
3.28-3.540.31331600.26941934X-RAY DIFFRACTION96
3.54-3.890.30891330.22761906X-RAY DIFFRACTION94
3.89-4.460.20791560.19891924X-RAY DIFFRACTION96
4.46-5.610.22151540.19772001X-RAY DIFFRACTION98

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