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- PDB-6y7w: Fragment KCL_1337 in complex with MAP kinase p38-alpha -

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Basic information

Entry
Database: PDB / ID: 6y7w
TitleFragment KCL_1337 in complex with MAP kinase p38-alpha
ComponentsMitogen-activated protein kinase 14MAPK14
KeywordsTRANSFERASE / FBDD / FRAGMENT BASED DRUG DESIGN / P38 / MAPK14 / KINASE
Function / homology
Function and homology information


DSCAM interactions / p38MAPK events / Activation of the AP-1 family of transcription factors / Platelet sensitization by LDL / RHO GTPases Activate NADPH Oxidases / ERK/MAPK targets / activated TAK1 mediates p38 MAPK activation / NOD1/2 Signaling Pathway / ADP signalling through P2Y purinoceptor 1 / Oxidative Stress Induced Senescence ...DSCAM interactions / p38MAPK events / Activation of the AP-1 family of transcription factors / Platelet sensitization by LDL / RHO GTPases Activate NADPH Oxidases / ERK/MAPK targets / activated TAK1 mediates p38 MAPK activation / NOD1/2 Signaling Pathway / ADP signalling through P2Y purinoceptor 1 / Oxidative Stress Induced Senescence / Regulation of TP53 Activity through Phosphorylation / Myogenesis / VEGFA-VEGFR2 Pathway / regulation of synaptic membrane adhesion / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / cartilage condensation / cellular response to UV-B / stress-activated protein kinase signaling cascade / mitogen-activated protein kinase p38 binding / positive regulation of myoblast fusion / negative regulation of hippo signaling / positive regulation of myotube differentiation / NFAT protein binding / glucose import / response to dietary excess / regulation of cytokine production involved in inflammatory response / p38MAPK cascade / fatty acid oxidation / cellular response to lipoteichoic acid / response to muramyl dipeptide / regulation of ossification / MAP kinase activity / mitogen-activated protein kinase / cellular response to vascular endothelial growth factor stimulus / positive regulation of myoblast differentiation / chondrocyte differentiation / vascular endothelial growth factor receptor signaling pathway / stress-activated MAPK cascade / skeletal muscle tissue development / signal transduction in response to DNA damage / lipopolysaccharide-mediated signaling pathway / positive regulation of cardiac muscle cell proliferation / striated muscle cell differentiation / response to muscle stretch / positive regulation of brown fat cell differentiation / Neutrophil degranulation / positive regulation of interleukin-12 production / osteoclast differentiation / positive regulation of erythrocyte differentiation / placenta development / DNA damage checkpoint signaling / cellular response to ionizing radiation / stem cell differentiation / positive regulation of glucose import / negative regulation of canonical Wnt signaling pathway / response to insulin / bone development / cell morphogenesis / osteoblast differentiation / cellular response to virus / spindle pole / positive regulation of protein import into nucleus / glucose metabolic process / positive regulation of reactive oxygen species metabolic process / MAPK cascade / cellular response to tumor necrosis factor / kinase activity / protein phosphatase binding / peptidyl-serine phosphorylation / angiogenesis / cellular response to lipopolysaccharide / response to lipopolysaccharide / transcription by RNA polymerase II / protein kinase activity / intracellular signal transduction / nuclear speck / protein serine kinase activity / protein serine/threonine kinase activity / glutamatergic synapse / apoptotic process / DNA damage response / positive regulation of gene expression / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / enzyme binding / positive regulation of transcription by RNA polymerase II / mitochondrion / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Mitogen-activated protein kinase 14 / Mitogen-activated protein (MAP) kinase p38-like / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase 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
Chem-OFW / Chem-SB4 / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.39 Å
AuthorsDe Nicola, G.F. / Nichols, C.E.
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
British Heart FoundationSP/14/2/30922, FS/14/29/30896 United Kingdom
Medical Research Council (MRC, United Kingdom)MC_PC_17164 United Kingdom
CitationJournal: J.Med.Chem. / Year: 2020
Title: Mining the PDB for Tractable Cases Where X-ray Crystallography Combined with Fragment Screens Can Be Used to Systematically Design Protein-Protein Inhibitors: Two Test Cases Illustrated by IL1 ...Title: Mining the PDB for Tractable Cases Where X-ray Crystallography Combined with Fragment Screens Can Be Used to Systematically Design Protein-Protein Inhibitors: Two Test Cases Illustrated by IL1 beta-IL1R and p38 alpha-TAB1 Complexes.
Authors: Nichols, C. / Ng, J. / Keshu, A. / Kelly, G. / Conte, M.R. / Marber, M.S. / Fraternali, F. / De Nicola, G.F.
History
DepositionMar 2, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 11, 2020Provider: repository / Type: Initial release
Revision 1.1Sep 30, 2020Group: Database references / Derived calculations
Category: citation / citation_author ...citation / citation_author / pdbx_struct_conn_angle / struct_conn
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_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_symmetry
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 14
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,4028
Polymers41,3221
Non-polymers1,0807
Water4,504250
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1180 Å2
ΔGint-40 kcal/mol
Surface area17010 Å2
MethodPISA
Unit cell
Length a, b, c (Å)80.881, 102.043, 103.947
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222
Space group name HallI22
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z
#4: -x,-y,z
#5: x+1/2,y+1/2,z+1/2
#6: x+1/2,-y+1/2,-z+1/2
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,z+1/2
Components on special symmetry positions
IDModelComponents
11A-675-

HOH

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Mitogen-activated protein kinase 14 / MAPK14 / MAPK 14 / CRK1 / Mitogen-activated protein kinase p38 alpha / MAP kinase p38 alpha


Mass: 41322.098 Da / Num. of mol.: 1 / Mutation: C162S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Mapk14, Crk1, Csbp1, Csbp2 / Production host: Escherichia coli (E. coli)
References: UniProt: P47811, mitogen-activated protein kinase

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Non-polymers , 5 types, 257 molecules

#2: Chemical ChemComp-SB4 / 4-(4-FLUOROPHENYL)-1-(4-PIPERIDINYL)-5-(2-AMINO-4-PYRIMIDINYL)-IMIDAZOLE / SB220025


Mass: 338.382 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H19FN6
#3: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca
#4: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-OFW / (2~{R})-~{N}-[(2-azanyl-2-adamantyl)methyl]-4-[6-[2,5-bis(oxidanylidene)pyrrolidin-1-yl]pyridin-3-yl]sulfonyl-2-methyl-morpholine-2-carboxamide


Mass: 545.651 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H35N5O6S / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 250 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.6 Å3/Da / Density % sol: 52.6 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 15% PEG400, 5% PEG550-MME, 0.1M REMARK 280 CALCIUM ACETATE, 0.1M MES PH6.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.91587 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Sep 22, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91587 Å / Relative weight: 1
ReflectionResolution: 1.39→63.83 Å / Num. obs: 86376 / % possible obs: 100 % / Redundancy: 6.4 % / Biso Wilson estimate: 19.42 Å2 / CC1/2: 1 / Net I/σ(I): 14.8
Reflection shellResolution: 1.39→1.41 Å / Redundancy: 6 % / Mean I/σ(I) obs: 1.1 / Num. unique obs: 4293 / CC1/2: 0.7 / % possible all: 99.7

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Processing

Software
NameVersionClassification
DIALSdata collection
PHENIX1.15.2_3472refinement
DIALSdata reduction
DIALSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6SOV

6sov


Resolution: 1.39→63.83 Å / SU ML: 0.1486 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 21.9514
RfactorNum. reflection% reflection
Rfree0.2188 4269 4.94 %
Rwork0.1948 --
obs0.1959 86340 99.93 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 24.26 Å2
Refinement stepCycle: LAST / Resolution: 1.39→63.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2753 0 68 250 3071
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00552984
X-RAY DIFFRACTIONf_angle_d0.85074077
X-RAY DIFFRACTIONf_chiral_restr0.0769456
X-RAY DIFFRACTIONf_plane_restr0.0049530
X-RAY DIFFRACTIONf_dihedral_angle_d3.1631781
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.39-1.410.33031510.31942670X-RAY DIFFRACTION99.4
1.41-1.420.35061260.30292723X-RAY DIFFRACTION99.75
1.42-1.440.30361510.29932711X-RAY DIFFRACTION99.97
1.44-1.460.29091710.28192685X-RAY DIFFRACTION99.83
1.46-1.480.29941670.27152648X-RAY DIFFRACTION99.89
1.48-1.50.2651510.25282720X-RAY DIFFRACTION99.83
1.5-1.520.25491430.24412700X-RAY DIFFRACTION99.93
1.52-1.540.26221470.24252723X-RAY DIFFRACTION99.97
1.54-1.570.26721300.22812718X-RAY DIFFRACTION99.89
1.57-1.590.24811300.23222713X-RAY DIFFRACTION99.96
1.59-1.620.24551510.21862723X-RAY DIFFRACTION100
1.62-1.650.23711330.2262720X-RAY DIFFRACTION99.96
1.65-1.680.25211430.22552706X-RAY DIFFRACTION99.86
1.68-1.710.23871400.22212722X-RAY DIFFRACTION99.97
1.71-1.750.26441580.21072688X-RAY DIFFRACTION100
1.75-1.790.23161400.20312751X-RAY DIFFRACTION99.97
1.79-1.840.23441410.19522725X-RAY DIFFRACTION100
1.84-1.890.21391290.19372756X-RAY DIFFRACTION99.93
1.89-1.940.21691390.1932735X-RAY DIFFRACTION100
1.94-20.221230.18882719X-RAY DIFFRACTION100
2-2.080.23911300.18272772X-RAY DIFFRACTION100
2.08-2.160.21211590.17972696X-RAY DIFFRACTION100
2.16-2.260.20271360.1782754X-RAY DIFFRACTION100
2.26-2.380.17011370.1812780X-RAY DIFFRACTION100
2.38-2.530.23881120.19412793X-RAY DIFFRACTION100
2.53-2.720.21031650.19632712X-RAY DIFFRACTION100
2.72-2.990.2251160.19612798X-RAY DIFFRACTION100
2.99-3.430.19951380.1882782X-RAY DIFFRACTION100
3.43-4.320.18161630.16382795X-RAY DIFFRACTION100
4.32-63.830.23081490.19422933X-RAY DIFFRACTION99.84

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