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- PDB-6ges: Crystal structure of ERK1 covalently bound to SM1-71 -

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Basic information

Entry
Database: PDB / ID: 6ges
TitleCrystal structure of ERK1 covalently bound to SM1-71
ComponentsMitogen-activated protein kinase 3
KeywordsTRANSFERASE / kinase / covalent inhibitor / MAPK / Structural Genomics / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


positive regulation of xenophagy / xenophagy / Suppression of apoptosis / RAF-independent MAPK1/3 activation / Signaling by Activin / Gastrin-CREB signalling pathway via PKC and MAPK / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / ERKs are inactivated / response to epidermal growth factor ...positive regulation of xenophagy / xenophagy / Suppression of apoptosis / RAF-independent MAPK1/3 activation / Signaling by Activin / Gastrin-CREB signalling pathway via PKC and MAPK / cardiac neural crest cell development involved in heart development / caveolin-mediated endocytosis / ERKs are inactivated / response to epidermal growth factor / Signaling by MAP2K mutants / Signaling by NODAL / RSK activation / Golgi Cisternae Pericentriolar Stack Reorganization / regulation of cellular pH / positive regulation of macrophage proliferation / positive regulation of cyclase activity / outer ear morphogenesis / Regulation of the apoptosome activity / cartilage development / regulation of Golgi inheritance / interleukin-1-mediated signaling pathway / trachea formation / Negative feedback regulation of MAPK pathway / regulation of cytoskeleton organization / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / IFNG signaling activates MAPKs / Frs2-mediated activation / positive regulation of macrophage chemotaxis / lung morphogenesis / ERBB2-ERBB3 signaling pathway / response to exogenous dsRNA / face development / Activation of the AP-1 family of transcription factors / MAPK3 (ERK1) activation / ERK/MAPK targets / RUNX2 regulates osteoblast differentiation / pseudopodium / positive regulation of telomere capping / Bergmann glial cell differentiation / thyroid gland development / Advanced glycosylation endproduct receptor signaling / RHO GTPases Activate NADPH Oxidases / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / Regulation of HSF1-mediated heat shock response / regulation of ossification / RHO GTPases Activate WASPs and WAVEs / MAP kinase activity / phosphatase binding / mitogen-activated protein kinase / BMP signaling pathway / Signal attenuation / Nuclear events stimulated by ALK signaling in cancer / stress-activated MAPK cascade / Schwann cell development / Growth hormone receptor signaling / signal transduction in response to DNA damage / peptidyl-tyrosine autophosphorylation / lipopolysaccharide-mediated signaling pathway / sensory perception of pain / negative regulation of TORC1 signaling / positive regulation of telomerase activity / ERK1 and ERK2 cascade / cellular response to cadmium ion / cellular response to amino acid starvation / positive regulation of telomere maintenance via telomerase / myelination / NPAS4 regulates expression of target genes / RNA Polymerase I Promoter Opening / NCAM signaling for neurite out-growth / phosphotyrosine residue binding / ESR-mediated signaling / insulin-like growth factor receptor signaling pathway / thymus development / Regulation of PTEN gene transcription / Signal transduction by L1 / caveola / Negative regulation of FGFR3 signaling / Downregulation of SMAD2/3:SMAD4 transcriptional activity / FCERI mediated MAPK activation / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / FCGR3A-mediated phagocytosis / Negative regulation of FGFR1 signaling / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / modulation of chemical synaptic transmission / MAP2K and MAPK activation / Oncogene Induced Senescence / Regulation of actin dynamics for phagocytic cup formation / ISG15 antiviral mechanism / cellular response to reactive oxygen species / cellular response to mechanical stimulus / Negative regulation of MAPK pathway / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants
Similarity search - Function
Mitogen-activated protein (MAP) kinase, ERK1/2 / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain ...Mitogen-activated protein (MAP) kinase, ERK1/2 / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-6H3 / Chem-EWH / Mitogen-activated protein kinase 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.07 Å
AuthorsChaikuad, A. / Suman, R. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Gray, N.S. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: Cell Chem Biol / Year: 2019
Title: Leveraging Compound Promiscuity to Identify Targetable Cysteines within the Kinome.
Authors: Rao, S. / Gurbani, D. / Du, G. / Everley, R.A. / Browne, C.M. / Chaikuad, A. / Tan, L. / Schroder, M. / Gondi, S. / Ficarro, S.B. / Sim, T. / Kim, N.D. / Berberich, M.J. / Knapp, S. / Marto, ...Authors: Rao, S. / Gurbani, D. / Du, G. / Everley, R.A. / Browne, C.M. / Chaikuad, A. / Tan, L. / Schroder, M. / Gondi, S. / Ficarro, S.B. / Sim, T. / Kim, N.D. / Berberich, M.J. / Knapp, S. / Marto, J.A. / Westover, K.D. / Sorger, P.K. / Gray, N.S.
History
DepositionApr 27, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 27, 2019Provider: repository / Type: Initial release
Revision 1.1May 1, 2019Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jul 3, 2019Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / database_PDB_rev / database_PDB_rev_record / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first / _citation_author.name
Revision 1.3Jan 17, 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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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

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Assembly

Deposited unit
A: Mitogen-activated protein kinase 3
B: Mitogen-activated protein kinase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)88,45412
Polymers86,5552
Non-polymers1,89810
Water5,621312
1
A: Mitogen-activated protein kinase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,4286
Polymers43,2781
Non-polymers1,1505
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Mitogen-activated protein kinase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,0266
Polymers43,2781
Non-polymers7485
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)61.974, 94.041, 64.916
Angle α, β, γ (deg.)90.00, 91.80, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: 0 / Ens-ID: 1 / Beg auth comp-ID: PRO / Beg label comp-ID: PRO / End auth comp-ID: GLY / End label comp-ID: GLY / Refine code: 0 / Auth seq-ID: 25 - 374 / Label seq-ID: 26 - 375

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

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Mitogen-activated protein kinase 3 / MAPK 3 / ERT2 / Extracellular signal-regulated kinase 1 / ERK-1 / Insulin-stimulated MAP2 kinase / ...MAPK 3 / ERT2 / Extracellular signal-regulated kinase 1 / ERK-1 / Insulin-stimulated MAP2 kinase / MAP kinase isoform p44 / p44-MAPK / Microtubule-associated protein 2 kinase / p44-ERK1


Mass: 43277.566 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK3, ERK1, PRKM3 / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): R3-pRARE2
References: UniProt: P27361, mitogen-activated protein kinase

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Non-polymers , 5 types, 322 molecules

#2: Chemical ChemComp-6H3 / N-{2-[(5-chloro-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)amino]phenyl}propanamide


Mass: 465.978 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H28ClN7O
#3: Chemical ChemComp-EWH / ~{N}-[2-[[5-chloranyl-2-[[4-(4-methylpiperazin-1-yl)phenyl]amino]pyrimidin-4-yl]amino]phenyl]prop-2-enamide / SM1-71


Mass: 463.963 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H26ClN7O
#4: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 312 / Source method: isolated from a natural source / Formula: H2O

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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: 2.18 Å3/Da / Density % sol: 43.69 %
Crystal growTemperature: 277.14 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 34% PEG 4k, 0.2M Li2SO4, 0.1M tris 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.99986 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 18, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99986 Å / Relative weight: 1
ReflectionResolution: 2.07→47.02 Å / Num. obs: 44884 / % possible obs: 98.9 % / Redundancy: 5.4 % / Biso Wilson estimate: 35.9 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.061 / Net I/σ(I): 13.5
Reflection shellResolution: 2.07→2.13 Å / Redundancy: 5.4 % / Rmerge(I) obs: 0.786 / Mean I/σ(I) obs: 2 / Num. unique obs: 3496 / CC1/2: 0.799 / % possible all: 99.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0222refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4qtb

4qtb


Resolution: 2.07→47.02 Å / Cor.coef. Fo:Fc: 0.971 / Cor.coef. Fo:Fc free: 0.951 / SU B: 10.836 / SU ML: 0.142 / Cross valid method: THROUGHOUT / ESU R: 0.209 / ESU R Free: 0.171 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21261 2228 5 %RANDOM
Rwork0.16954 ---
obs0.17177 42634 98.84 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 45.749 Å2
Baniso -1Baniso -2Baniso -3
1--2.04 Å2-0 Å2-0.44 Å2
2--1.21 Å2-0 Å2
3---0.86 Å2
Refinement stepCycle: 1 / Resolution: 2.07→47.02 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5700 0 129 312 6141
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0155974
X-RAY DIFFRACTIONr_bond_other_d0.0010.0175405
X-RAY DIFFRACTIONr_angle_refined_deg1.4021.7458076
X-RAY DIFFRACTIONr_angle_other_deg0.4591.71412675
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4135700
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.80118.803234
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.12815917
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.5421543
X-RAY DIFFRACTIONr_chiral_restr0.0690.2762
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0216920
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021100
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.1153.2982801
X-RAY DIFFRACTIONr_mcbond_other2.1153.3012802
X-RAY DIFFRACTIONr_mcangle_it2.9914.933499
X-RAY DIFFRACTIONr_mcangle_other2.9914.9333500
X-RAY DIFFRACTIONr_scbond_it3.1783.7863173
X-RAY DIFFRACTIONr_scbond_other3.1763.7863173
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.9235.5274577
X-RAY DIFFRACTIONr_long_range_B_refined6.34341.3156656
X-RAY DIFFRACTIONr_long_range_B_other6.34341.3226657
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Number: 11756 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.07 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.07→2.124 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.293 152 -
Rwork0.27 3162 -
obs--99.25 %
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)
13.7605-1.5201-0.65664.9839-2.39423.6826-0.3094-0.02510.45710.06460.1294-0.34220.124-0.14360.180.0279-0.0142-0.03180.1897-0.02510.075753.82126.22327.675
20.42720.0306-0.17010.1164-0.02510.5555-0.03070.0048-0.0008-0.01360.03310.0091-0.0250.0082-0.00230.0171-0.0147-0.01150.25290.00470.011660.34410.3474.856
31.1353-0.38491.57981.9693-0.51418.49650.0772-0.01420.0184-0.08250.04080.170.1359-0.3696-0.11810.0080.0045-0.00880.15370.02240.07736.90915.91915.233
46.126-2.2363-0.50814.4772.2961.8318-0.30330.0492-0.66430.07150.0870.3969-0.12410.01640.21630.0441-0.00610.01380.19590.02070.091338.714-17.052-5.876
50.7355-0.05030.08610.049-0.12170.5578-0.00080.01190.02050.01320.013-0.00720.01710.0267-0.01220.0163-0.0058-0.00810.2108-0.00370.004933.328-1.229-28.695
60.9663-0.2814-1.93972.23870.943.96360.0699-0.09250.0435-0.11480.0666-0.3435-0.16660.1997-0.13660.02860.00720.00210.24750.01480.071556.048-6.243-17.639
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A25 - 71
2X-RAY DIFFRACTION2A72 - 349
3X-RAY DIFFRACTION3A350 - 374
4X-RAY DIFFRACTION4B25 - 72
5X-RAY DIFFRACTION5B73 - 347
6X-RAY DIFFRACTION6B348 - 374

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