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- PDB-6t6d: Crystal structure of the ACVR1 (ALK2) kinase in complex with the ... -

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Basic information

Entry
Database: PDB / ID: 6t6d
TitleCrystal structure of the ACVR1 (ALK2) kinase in complex with the compound M4K2149
ComponentsActivin receptor type I
KeywordsSIGNALING PROTEIN / KINASE / BMP / INHIBITOR / SIGNALLING
Function / homology
Function and homology information


endocardial cushion cell fate commitment / mitral valve morphogenesis / BMP receptor complex / cardiac muscle cell fate commitment / atrial septum primum morphogenesis / endocardial cushion fusion / positive regulation of cardiac epithelial to mesenchymal transition / acute inflammatory response / positive regulation of determination of dorsal identity / smooth muscle cell differentiation ...endocardial cushion cell fate commitment / mitral valve morphogenesis / BMP receptor complex / cardiac muscle cell fate commitment / atrial septum primum morphogenesis / endocardial cushion fusion / positive regulation of cardiac epithelial to mesenchymal transition / acute inflammatory response / positive regulation of determination of dorsal identity / smooth muscle cell differentiation / activin receptor complex / endocardial cushion formation / transforming growth factor beta receptor activity, type I / activin receptor activity, type I / activin receptor activity, type II / BMP receptor activity / receptor protein serine/threonine kinase / transmembrane receptor protein serine/threonine kinase activity / transforming growth factor beta receptor activity, type II / pharyngeal system development / transforming growth factor beta receptor activity, type III / activin binding / cellular response to BMP stimulus / negative regulation of activin receptor signaling pathway / activin receptor signaling pathway / embryonic heart tube morphogenesis / gastrulation with mouth forming second / dorsal/ventral pattern formation / transforming growth factor beta binding / determination of left/right symmetry / neural crest cell migration / atrioventricular valve morphogenesis / branching involved in blood vessel morphogenesis / ventricular septum morphogenesis / negative regulation of G1/S transition of mitotic cell cycle / SMAD binding / germ cell development / positive regulation of intracellular signal transduction / peptide hormone binding / mesoderm formation / positive regulation of SMAD protein signal transduction / regulation of ossification / BMP signaling pathway / positive regulation of bone mineralization / negative regulation of signal transduction / positive regulation of osteoblast differentiation / transforming growth factor beta receptor signaling pathway / protein tyrosine kinase binding / negative regulation of extrinsic apoptotic signaling pathway / cellular response to growth factor stimulus / osteoblast differentiation / apical part of cell / heart development / in utero embryonic development / cell differentiation / protein kinase activity / positive regulation of cell migration / cadherin binding / 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 / Phosphorylase Kinase; domain 1 ...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 / 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-MM8 / Activin receptor type-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.56 Å
AuthorsAdamson, R.J. / Williams, E.P. / Smil, D. / Burgess-Brown, N. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Bullock, A.N.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Targeting ALK2: An Open Science Approach to Developing Therapeutics for the Treatment of Diffuse Intrinsic Pontine Glioma.
Authors: Ensan, D. / Smil, D. / Zepeda-Velazquez, C.A. / Panagopoulos, D. / Wong, J.F. / Williams, E.P. / Adamson, R. / Bullock, A.N. / Kiyota, T. / Aman, A. / Roberts, O.G. / Edwards, A.M. / ...Authors: Ensan, D. / Smil, D. / Zepeda-Velazquez, C.A. / Panagopoulos, D. / Wong, J.F. / Williams, E.P. / Adamson, R. / Bullock, A.N. / Kiyota, T. / Aman, A. / Roberts, O.G. / Edwards, A.M. / O'Meara, J.A. / Isaac, M.B. / Al-Awar, R.
History
DepositionOct 18, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 30, 2019Provider: repository / Type: Initial release
Revision 1.1May 13, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2May 27, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Jan 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
Revision 1.4Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Activin receptor type I
B: Activin receptor type I
C: Activin receptor type I
D: Activin receptor type I
hetero molecules


Theoretical massNumber of molelcules
Total (without water)140,81719
Polymers138,1514
Non-polymers2,66715
Water54030
1
A: Activin receptor type I
hetero molecules


  • defined by author
  • Evidence: gel filtration, Disulphide bonds between chains in the ASU are non-physiological. Monomer observed in gel filtration, mass spectrometry, Disulphide bonds between chains in the ASU are non- ...Evidence: gel filtration, Disulphide bonds between chains in the ASU are non-physiological. Monomer observed in gel filtration, mass spectrometry, Disulphide bonds between chains in the ASU are non-physiological. Monomer observed by mass spectrometry
  • 35.2 kDa, 1 polymers
  • Search similar-shape structures of this assembly by Omokage search (details)
Theoretical massNumber of molelcules
Total (without water)35,2285
Polymers34,5381
Non-polymers6914
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Activin receptor type I
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,2285
Polymers34,5381
Non-polymers6914
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Activin receptor type I
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,2285
Polymers34,5381
Non-polymers6914
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Activin receptor type I
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1324
Polymers34,5381
Non-polymers5953
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)198.091, 101.882, 84.271
Angle α, β, γ (deg.)90.000, 111.429, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z

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Components

#1: Protein
Activin receptor type I


Mass: 34537.633 Da / Num. of mol.: 4 / Mutation: Q207D
Source method: isolated from a genetically manipulated source
Details: Chains E, F, G and H contain ligand 149 bound to the kinase active site and SO4 as part of the crystal packing.
Source: (gene. exp.) Homo sapiens (human) / Gene: ACVR1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q04771, receptor protein serine/threonine kinase
#2: Chemical
ChemComp-MM8 / 2-methoxy-4-[4-methyl-5-(4-piperazin-1-ylphenyl)pyridin-3-yl]benzamide


Mass: 402.489 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C24H26N4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 11 / Source method: isolated from a natural source / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 30 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.92 Å3/Da / Density % sol: 57.9 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 4.9
Details: 0.1M citrate pH 4.9, 1M ammonium sulfate, 0.2M sodium/potassium tartrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jan 21, 2019
RadiationMonochromator: double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2.56→89.13 Å / Num. obs: 50340 / % possible obs: 100 % / Redundancy: 13.3 % / Biso Wilson estimate: 58.84 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.197 / Rpim(I) all: 0.056 / Rrim(I) all: 0.205 / Χ2: 0.99 / Net I/σ(I): 8.8
Reflection shellResolution: 2.56→2.63 Å / Redundancy: 13.5 % / Rmerge(I) obs: 3.197 / Mean I/σ(I) obs: 1.3 / Num. unique obs: 3699 / CC1/2: 0.87 / Rpim(I) all: 0.901 / Rrim(I) all: 3.323 / Χ2: 1 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.16_3549refinement
PHENIX1.16_3549refinement
xia21.12data reduction
Aimless0.7.3data scaling
PHASER1.13_2998phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6SRH

6srh


Resolution: 2.56→78.45 Å / SU ML: 0.4258 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 35.6209
RfactorNum. reflection% reflectionSelection details
Rfree0.2717 2489 4.96 %Random selection
Rwork0.2217 ---
obs0.2242 50137 99.35 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 73.66 Å2
Refinement stepCycle: LAST / Resolution: 2.56→78.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8915 0 175 30 9120
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00179322
X-RAY DIFFRACTIONf_angle_d0.459412710
X-RAY DIFFRACTIONf_chiral_restr0.03861442
X-RAY DIFFRACTIONf_plane_restr0.00231579
X-RAY DIFFRACTIONf_dihedral_angle_d10.23585468
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.56-2.610.43181090.40132523X-RAY DIFFRACTION94.61
2.61-2.660.4281450.37762603X-RAY DIFFRACTION98.96
2.66-2.720.46921390.37182665X-RAY DIFFRACTION99.33
2.72-2.780.45191370.33362588X-RAY DIFFRACTION99.27
2.78-2.850.35921420.30732662X-RAY DIFFRACTION99.15
2.85-2.930.36131330.27562639X-RAY DIFFRACTION99.5
2.93-3.010.36511470.27422669X-RAY DIFFRACTION99.54
3.01-3.110.28911490.2622576X-RAY DIFFRACTION99.63
3.11-3.220.30671430.27622657X-RAY DIFFRACTION99.64
3.22-3.350.30491230.25372661X-RAY DIFFRACTION99.86
3.35-3.50.29571160.23212699X-RAY DIFFRACTION99.89
3.5-3.690.27891240.22562663X-RAY DIFFRACTION99.89
3.69-3.920.28211670.20132619X-RAY DIFFRACTION99.71
3.92-4.220.24351580.18922660X-RAY DIFFRACTION99.89
4.22-4.650.21251470.17572657X-RAY DIFFRACTION99.96
4.65-5.320.2381480.18372666X-RAY DIFFRACTION99.89
5.32-6.70.24271370.20352689X-RAY DIFFRACTION99.89
6.7-78.450.20691250.18392752X-RAY DIFFRACTION99.55

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