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- PDB-6ylc: Biochemical, Cellular and Structural Characterization of Novel ER... -

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Basic information

Entry
Database: PDB / ID: 6ylc
TitleBiochemical, Cellular and Structural Characterization of Novel ERK3 Inhibitors
ComponentsMitogen-activated protein kinase 6
KeywordsTRANSFERASE / human mitogen activated protein kinase 6 (MAPK6) / ERK3 / inhibitor
Function / homology
Function and homology information


septin cytoskeleton / positive regulation of dendritic spine development / MAP kinase activity / mitogen-activated protein kinase / MAPK6/MAPK4 signaling / protein phosphorylation / intracellular signal transduction / protein heterodimerization activity / protein serine kinase activity / protein serine/threonine kinase activity ...septin cytoskeleton / positive regulation of dendritic spine development / MAP kinase activity / mitogen-activated protein kinase / MAPK6/MAPK4 signaling / protein phosphorylation / intracellular signal transduction / protein heterodimerization activity / protein serine kinase activity / protein serine/threonine kinase activity / protein kinase binding / signal transduction / protein-containing complex / nucleoplasm / ATP binding / nucleus / cytoplasm / cytosol
Similarity search - Function
Mitogen-activated protein (MAP) kinase, ERK3/4 / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain ...Mitogen-activated protein (MAP) kinase, ERK3/4 / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-OXW / Mitogen-activated protein kinase 6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.43 Å
AuthorsGraedler, U.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2020
Title: Biochemical, cellular and structural characterization of novel and selective ERK3 inhibitors.
Authors: Gradler, U. / Busch, M. / Leuthner, B. / Raba, M. / Burgdorf, L. / Lehmann, M. / Linde, N. / Esdar, C.
History
DepositionApr 7, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 23, 2020Provider: repository / Type: Initial release
Revision 1.1Sep 30, 2020Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.title
Revision 1.2Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Mitogen-activated protein kinase 6
B: Mitogen-activated protein kinase 6
C: Mitogen-activated protein kinase 6
D: Mitogen-activated protein kinase 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)146,4488
Polymers144,7754
Non-polymers1,6744
Water2,144119
1
A: Mitogen-activated protein kinase 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6122
Polymers36,1941
Non-polymers4181
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Mitogen-activated protein kinase 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6122
Polymers36,1941
Non-polymers4181
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Mitogen-activated protein kinase 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6122
Polymers36,1941
Non-polymers4181
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Mitogen-activated protein kinase 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6122
Polymers36,1941
Non-polymers4181
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)67.332, 101.423, 195.889
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein
Mitogen-activated protein kinase 6 / MAPK 6 / Extracellular signal-regulated kinase 3 / ERK-3 / MAP kinase isoform p97 / p97-MAPK


Mass: 36193.672 Da / Num. of mol.: 4 / Mutation: L290V
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK6, ERK3, PRKM6 / Production host: Escherichia coli (E. coli)
References: UniProt: Q16659, mitogen-activated protein kinase
#2: Chemical
ChemComp-OXW / 5-fluoranyl-2-[5-[[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]amino]-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]benzenecarbonitrile


Mass: 418.430 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H19FN10 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 119 / 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: 2.49 Å3/Da / Density % sol: 50.67 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 100 mM Bis-Tris (pH 6), 100 mM Lithium acetate, 18%v/v Sokalan CP42, 3%v/v Glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.966 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Jul 25, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.966 Å / Relative weight: 1
ReflectionResolution: 2.43→97.94 Å / Num. obs: 43014 / % possible obs: 99.5 % / Redundancy: 5 % / Biso Wilson estimate: 82.32 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.044 / Rpim(I) all: 0.024 / Rrim(I) all: 0.053 / Rsym value: 0.044 / Net I/σ(I): 19.7
Reflection shellResolution: 2.434→2.476 Å / Redundancy: 5.3 % / Rmerge(I) obs: 0.619 / Mean I/σ(I) obs: 2.3 / Num. measured all: 685 / Num. unique obs: 128 / CC1/2: 0.509 / Rpim(I) all: 0.552 / Rrim(I) all: 1.28 / Rsym value: 0.619 / Net I/σ(I) obs: 1.2 / % possible all: 99.7

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
XDSversion May 1, 2016data reduction
Aimlessversion 1.1.7data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6YKY

6yky


Resolution: 2.43→49.09 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.93 / SU R Cruickshank DPI: 0.654 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.62 / SU Rfree Blow DPI: 0.272 / SU Rfree Cruickshank DPI: 0.278
RfactorNum. reflection% reflectionSelection details
Rfree0.231 2185 5.08 %RANDOM
Rwork0.189 ---
obs0.191 43014 84.1 %-
Displacement parametersBiso max: 214.06 Å2 / Biso mean: 91.82 Å2 / Biso min: 34.62 Å2
Baniso -1Baniso -2Baniso -3
1-6.2843 Å20 Å20 Å2
2---1.5668 Å20 Å2
3----4.7176 Å2
Refine analyzeLuzzati coordinate error obs: 0.32 Å
Refinement stepCycle: final / Resolution: 2.43→49.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9209 0 124 119 9452
Biso mean--87.37 64.13 -
Num. residues----1157
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3347SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1582HARMONIC5
X-RAY DIFFRACTIONt_it9527HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1215SEMIHARMONIC5
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_contact10145SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d9527HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg12897HARMONIC21.14
X-RAY DIFFRACTIONt_omega_torsion2.92
X-RAY DIFFRACTIONt_other_torsion20.19
LS refinement shellResolution: 2.43→2.53 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.3247 37 4.3 %
Rwork0.2239 824 -
all0.2285 861 -
obs--15.19 %
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)
13.2710.1367-1.05954.1415-1.76965.08070.2765-0.2120.10420.1554-0.1595-0.1261-0.28310.2282-0.117-0.10250.02340.0405-0.33740.0445-0.311223.391-10.977-57.6216
22.92611.78-0.60054.4091-0.95825.8852-0.28980.0698-0.495-0.1878-0.0211-0.38410.62740.0580.3109-0.2113-0.00210.0755-0.3229-0.0541-0.2655-6.2494-45.3711-15.3199
36.33123.9273-1.62265.8202-0.60752.76480.03920.03450.5587-0.37690.30.7075-0.0228-0.0376-0.3392-0.1365-0.1708-0.134-0.29720.0732-0.348414.70213.6432-36.9871
42.55920.0716-0.0243.3577-0.06483.01880.1104-0.07190.1896-0.17950.03150.3187-0.0711-0.0399-0.1419-0.1884-0.0542-0.0218-0.17040.0499-0.2025.0408-8.7032-11.4423
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A15 - 320
2X-RAY DIFFRACTION2{ B|* }B16 - 321
3X-RAY DIFFRACTION3{ C|* }C14 - 319
4X-RAY DIFFRACTION4{ D|* }D13 - 321

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