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- PDB-6y7y: Fragments KCL_771 and KCL_802 in complex with MAP kinase p38-alpha -

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Basic information

Entry
Database: PDB / ID: 6y7y
TitleFragments KCL_771 and KCL_802 in complex with MAP kinase p38-alpha
ComponentsMitogen-activated protein kinase 14
KeywordsTRANSFERASE / FBDD / FRAGMENT BASED DRUG DESIGN / P38 / MAPK14 / KINASE
Function / homology
Function and homology information


p38MAPK events / Activation of the AP-1 family of transcription factors / Platelet sensitization by LDL / RHO GTPases Activate NADPH Oxidases / ERK/MAPK targets / myoblast differentiation involved in skeletal muscle regeneration / Regulation of MITF-M-dependent genes involved in pigmentation / activated TAK1 mediates p38 MAPK activation / NOD1/2 Signaling Pathway / Oxidative Stress Induced Senescence ...p38MAPK events / Activation of the AP-1 family of transcription factors / Platelet sensitization by LDL / RHO GTPases Activate NADPH Oxidases / ERK/MAPK targets / myoblast differentiation involved in skeletal muscle regeneration / Regulation of MITF-M-dependent genes involved in pigmentation / activated TAK1 mediates p38 MAPK activation / NOD1/2 Signaling Pathway / Oxidative Stress Induced Senescence / ADP signalling through P2Y purinoceptor 1 / 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 / positive regulation of myoblast fusion / cellular response to UV-B / mitogen-activated protein kinase p38 binding / NFAT protein binding / positive regulation of myotube differentiation / D-glucose import / regulation of cytokine production involved in inflammatory response / p38MAPK cascade / fatty acid oxidation / cellular response to lipoteichoic acid / response to muramyl dipeptide / response to dietary excess / MAP kinase activity / regulation of ossification / cellular response to vascular endothelial growth factor stimulus / mitogen-activated protein kinase / JUN kinase activity / negative regulation of hippo signaling / positive regulation of myoblast differentiation / chondrocyte differentiation / vascular endothelial growth factor receptor signaling pathway / skeletal muscle tissue development / stress-activated MAPK cascade / 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 / lipopolysaccharide-mediated signaling pathway / positive regulation of erythrocyte differentiation / DNA damage checkpoint signaling / cellular response to ionizing radiation / positive regulation of D-glucose import / stem cell differentiation / response to insulin / placenta development / negative regulation of canonical Wnt signaling pathway / bone development / cell morphogenesis / cellular response to virus / spindle pole / positive regulation of protein import into nucleus / glucose metabolic process / positive regulation of reactive oxygen species metabolic process / osteoblast differentiation / MAPK cascade / kinase activity / cellular response to tumor necrosis factor / cellular response to lipopolysaccharide / peptidyl-serine phosphorylation / protein phosphatase binding / angiogenesis / 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 / apoptotic process / DNA damage response / positive regulation of gene expression / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / glutamatergic synapse / 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. / : / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site ...Mitogen-activated protein kinase 14 / Mitogen-activated protein (MAP) kinase p38-like / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / 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-LOT / (2-azanyl-2-adamantyl)methanol / Chem-SB4 / Mitogen-activated protein kinase 14
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.51 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)42,54810
Polymers41,3221
Non-polymers1,2269
Water4,053225
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1200 Å2
ΔGint-44 kcal/mol
Surface area16630 Å2
MethodPISA
Unit cell
Length a, b, c (Å)80.380, 102.586, 104.731
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

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Mitogen-activated protein kinase 14 / 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 , 6 types, 234 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


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-OFQ / (2-azanyl-2-adamantyl)methanol


Mass: 181.275 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H19NO / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-LOT / 6-[2,5-bis(oxidanylidene)pyrrolidin-1-yl]pyridine-3-sulfonamide


Mass: 255.250 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H9N3O4S / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 225 / 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: 2.61 Å3/Da / Density % sol: 52.92 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 15% PEG400, 5% PEG550-MME, 0.1M 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: I24 / Wavelength: 0.9686 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Feb 8, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9686 Å / Relative weight: 1
ReflectionResolution: 1.51→63.27 Å / Num. obs: 65484 / % possible obs: 96.1 % / Redundancy: 3.3 % / Biso Wilson estimate: 15.11 Å2 / CC1/2: 1 / Net I/σ(I): 10.8
Reflection shellResolution: 1.51→1.54 Å / Redundancy: 3.2 % / Mean I/σ(I) obs: 1.5 / Num. unique obs: 3135 / CC1/2: 0.5 / % possible all: 92.9

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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: 1.51→63.27 Å / SU ML: 0.2545 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 29.4976
RfactorNum. reflection% reflection
Rfree0.2485 3146 4.82 %
Rwork0.2197 --
obs0.2211 65228 95.68 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 21.51 Å2
Refinement stepCycle: LAST / Resolution: 1.51→63.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2707 0 77 225 3009
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00652907
X-RAY DIFFRACTIONf_angle_d0.88383973
X-RAY DIFFRACTIONf_chiral_restr0.0522448
X-RAY DIFFRACTIONf_plane_restr0.0049525
X-RAY DIFFRACTIONf_dihedral_angle_d3.14192381
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.51-1.530.42011430.39092675X-RAY DIFFRACTION91.55
1.53-1.560.42571320.38062817X-RAY DIFFRACTION96.82
1.56-1.580.39021360.35652845X-RAY DIFFRACTION96.85
1.58-1.610.37371420.35252826X-RAY DIFFRACTION96.9
1.61-1.640.33861580.33132848X-RAY DIFFRACTION97.66
1.64-1.680.37941430.31872849X-RAY DIFFRACTION97.46
1.68-1.710.34911570.32612808X-RAY DIFFRACTION96.71
1.71-1.750.30811530.29932781X-RAY DIFFRACTION95.91
1.75-1.80.29641470.27392758X-RAY DIFFRACTION94.78
1.8-1.850.27271450.26242839X-RAY DIFFRACTION96.91
1.85-1.90.28811350.2472879X-RAY DIFFRACTION97.19
1.9-1.960.27741340.23482857X-RAY DIFFRACTION97.43
1.96-2.030.25511370.22462863X-RAY DIFFRACTION96.93
2.03-2.110.25961530.20192816X-RAY DIFFRACTION96.74
2.11-2.210.24681460.19832846X-RAY DIFFRACTION96.45
2.21-2.330.2321510.19222853X-RAY DIFFRACTION96.13
2.33-2.470.23411100.19272825X-RAY DIFFRACTION95.57
2.47-2.660.2051460.19042824X-RAY DIFFRACTION95.04
2.66-2.930.22831480.19592809X-RAY DIFFRACTION94.81
2.93-3.360.21091320.18672838X-RAY DIFFRACTION94.2
3.36-4.230.17721490.16672774X-RAY DIFFRACTION92.65
4.23-63.270.23421490.19722852X-RAY DIFFRACTION90.94

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