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- PDB-6eix: Crystal structure of the kinase domain of the Q207E mutant of ACV... -

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Basic information

Entry
Database: PDB / ID: 6eix
TitleCrystal structure of the kinase domain of the Q207E mutant of ACVR1 (ALK2) in complex with a 2-aminopyridine inhibitor K02288
ComponentsActivin receptor type-1
KeywordsSIGNALING PROTEIN / Kinase / ALK2 / Receptor / BMP / Structural Genomics / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


endocardial cushion cell fate commitment / mitral valve morphogenesis / endocardial cushion fusion / BMP receptor complex / atrial septum primum morphogenesis / BMP receptor activity / cardiac muscle cell fate commitment / acute inflammatory response / activin receptor activity, type I / positive regulation of cardiac epithelial to mesenchymal transition ...endocardial cushion cell fate commitment / mitral valve morphogenesis / endocardial cushion fusion / BMP receptor complex / atrial septum primum morphogenesis / BMP receptor activity / cardiac muscle cell fate commitment / acute inflammatory response / activin receptor activity, type I / positive regulation of cardiac epithelial to mesenchymal transition / positive regulation of determination of dorsal identity / transforming growth factor beta receptor activity, type I / activin receptor complex / endocardial cushion formation / smooth muscle cell differentiation / receptor protein serine/threonine kinase / transmembrane receptor protein serine/threonine kinase activity / pharyngeal system development / activin binding / cellular response to BMP stimulus / activin receptor signaling pathway / negative regulation of activin receptor signaling pathway / transforming growth factor beta binding / embryonic heart tube morphogenesis / gastrulation with mouth forming second / dorsal/ventral pattern formation / determination of left/right symmetry / neural crest cell migration / atrioventricular valve morphogenesis / branching involved in blood vessel morphogenesis / negative regulation of G1/S transition of mitotic cell cycle / ventricular septum morphogenesis / SMAD binding / germ cell development / peptide hormone binding / positive regulation of SMAD protein signal transduction / mesoderm formation / regulation of ossification / BMP signaling pathway / positive regulation of bone mineralization / positive regulation of osteoblast differentiation / negative regulation of signal transduction / transforming growth factor beta receptor signaling pathway / protein tyrosine kinase binding / negative regulation of extrinsic apoptotic signaling pathway / cellular response to growth factor stimulus / positive regulation of peptidyl-tyrosine phosphorylation / apical part of cell / heart development / in utero embryonic development / protein kinase activity / positive regulation of cell migration / cadherin binding / phosphorylation / protein serine/threonine kinase activity / positive regulation of DNA-templated transcription / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / ATP binding / metal ion binding / plasma membrane
Similarity search - Function
GS domain / Transforming growth factor beta type I GS-motif / GS domain profile. / GS motif / Activin types I and II receptor domain / Activin types I and II receptor domain / Ser/Thr protein kinase, TGFB receptor / Snake toxin-like superfamily / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain ...GS domain / Transforming growth factor beta type I GS-motif / GS domain profile. / GS motif / Activin types I and II receptor domain / Activin types I and II receptor domain / Ser/Thr protein kinase, TGFB receptor / Snake toxin-like superfamily / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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. / 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-A3F / Activin receptor type-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsWilliams, E.P. / Canning, P. / Sanvitale, C.E. / Krojer, T. / Allerston, C.K. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Bullock, A.N.
CitationJournal: To be published
Title: Crystal structure of the kinase domain of the Q207E mutant of ACVR1 (ALK2) in complex with K02288
Authors: Williams, E.P. / Canning, P. / Sanvitale, C.E. / Bullock, A.N.
History
DepositionSep 19, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 27, 2017Provider: repository / Type: Initial release
Revision 1.1Dec 13, 2017Group: Structure summary / Category: audit_author / Item: _audit_author.name
Revision 1.2Feb 28, 2018Group: Source and taxonomy / Category: entity_src_gen
Item: _entity_src_gen.pdbx_host_org_cell_line / _entity_src_gen.pdbx_host_org_strain
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
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: Activin receptor type-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,43111
Polymers38,5201
Non-polymers91110
Water1,15364
1


  • Idetical with deposited unit
  • defined by software
  • Evidence: gel filtration, mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1790 Å2
ΔGint29 kcal/mol
Surface area14280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.560, 66.990, 62.220
Angle α, β, γ (deg.)90.00, 91.04, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Activin receptor type-1 / Activin receptor type I / ACTR-I / Activin receptor-like kinase 2 / ALK-2 / Serine/threonine- ...Activin receptor type I / ACTR-I / Activin receptor-like kinase 2 / ALK-2 / Serine/threonine-protein kinase receptor R1 / SKR1 / TGF-B superfamily receptor type I / TSR-I


Mass: 38520.000 Da / Num. of mol.: 1 / Mutation: Q207E
Source method: isolated from a genetically manipulated source
Details: Missing residues at N and C terminus due to insufficient density to model them.
Source: (gene. exp.) Homo sapiens (human) / Gene: ACVR1, ACVRLK2 / Plasmid: pFB-LIC-Bse / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q04771, receptor protein serine/threonine kinase
#2: Chemical ChemComp-A3F / 3-[6-amino-5-(3,4,5-trimethoxyphenyl)pyridin-3-yl]phenol


Mass: 352.384 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H20N2O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 64 / 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: 2.21 Å3/Da / Density % sol: 44.35 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: 0.1M MES pH 6.5 -- 12%(w/v) PEG 20000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9778 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 21, 2012
Details: Kirkpatrick Baez bimorph mirror pair for horizontal and vertical focussing
RadiationMonochromator: Double Crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9778 Å / Relative weight: 1
ReflectionResolution: 2.3→19.78 Å / Num. obs: 14813 / % possible obs: 98.9 % / Observed criterion σ(I): 2 / Redundancy: 3 % / CC1/2: 0.984 / Rmerge(I) obs: 0.122 / Rpim(I) all: 0.082 / Rrim(I) all: 0.148 / Net I/σ(I): 5.4
Reflection shellResolution: 2.3→2.38 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.511 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 1444 / CC1/2: 0.749 / Rpim(I) all: 0.344 / Rrim(I) all: 0.619 / % possible all: 99.1

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Processing

Software
NameVersionClassification
REFMAC5.7.0032refinement
iMOSFLM7.2.1data reduction
Aimless7.0.044data scaling
PHASER7.0.044phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1IAS

1ias


Resolution: 2.3→19.78 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.892 / SU B: 13.579 / SU ML: 0.17 / SU R Cruickshank DPI: 0.3761 / Cross valid method: THROUGHOUT / ESU R: 0.376 / ESU R Free: 0.253 / SU Rfree Cruickshank DPI: 0.2529 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24944 749 5.1 %RANDOM
Rwork0.18825 ---
obs0.19135 14001 98.39 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 33.214 Å2
Baniso -1Baniso -2Baniso -3
1--0.83 Å20 Å20.08 Å2
2---3.68 Å20 Å2
3---4.51 Å2
Refinement stepCycle: 1 / Resolution: 2.3→19.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2464 0 62 64 2590
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0192583
X-RAY DIFFRACTIONr_bond_other_d0.0010.022459
X-RAY DIFFRACTIONr_angle_refined_deg1.1291.9673491
X-RAY DIFFRACTIONr_angle_other_deg0.72235638
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0845313
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.66124.018112
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.45715437
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.951516
X-RAY DIFFRACTIONr_chiral_restr0.0630.2388
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212878
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02591
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_it4.1318.521252
X-RAY DIFFRACTIONr_mcbond_other4.1288.5111251
X-RAY DIFFRACTIONr_mcangle_it5.34612.4321565
X-RAY DIFFRACTIONr_mcangle_other5.34612.4411566
X-RAY DIFFRACTIONr_scbond_it4.7089.2571331
X-RAY DIFFRACTIONr_scbond_other4.699.2581331
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other6.25813.1021927
X-RAY DIFFRACTIONr_long_range_B_refined7.59129.1682950
X-RAY DIFFRACTIONr_long_range_B_other7.5929.1812951
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.3→2.36 Å
RfactorNum. reflection% reflection
Rfree0.277 47 5 %
Rwork0.218 994 -
obs--97.56 %
Refinement TLS params.Method: refined / Origin x: 19.4143 Å / Origin y: 19.0257 Å / Origin z: -18.2558 Å
111213212223313233
T0.0456 Å2-0.0136 Å2-0.0042 Å2-0.0619 Å2-0.0224 Å2--0.0907 Å2
L0.5775 °20.2082 °2-0.2425 °2-0.4149 °2-0.004 °2--0.1575 °2
S0.0635 Å °-0.1033 Å °0.0422 Å °-0.0283 Å °-0.071 Å °0.0514 Å °-0.0079 Å °0.0349 Å °0.0075 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A172 - 196
2X-RAY DIFFRACTION1A197 - 258
3X-RAY DIFFRACTION1A259 - 297
4X-RAY DIFFRACTION1A298 - 359
5X-RAY DIFFRACTION1A360 - 377
6X-RAY DIFFRACTION1A378 - 499

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