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- PDB-8c7w: Crystal structure of the ACVR1 (ALK2) kinase in complex with the ... -

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Basic information

Entry
Database: PDB / ID: 8c7w
TitleCrystal structure of the ACVR1 (ALK2) kinase in complex with the compound M4K2304
ComponentsActivin receptor type I
KeywordsSIGNALING PROTEIN / BMP signalling Kinase Inhibitor
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 / Phosphorylase Kinase; domain 1 / 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 / 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-U0C / Activin receptor type-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.26 Å
AuthorsCros, J. / Williams, E.P. / Sweeney, M.N. / Smil, D. / Gonzalez-Alvarez, H. / Al-awar, R. / Bullock, A.N.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Innovative Medicines Initiative Switzerland
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of Conformationally Constrained ALK2 Inhibitors.
Authors: Gonzalez-Alvarez, H. / Ensan, D. / Xin, T. / Wong, J.F. / Zepeda-Velazquez, C.A. / Cros, J. / Sweeney, M.N. / Hoffer, L. / Kiyota, T. / Wilson, B.J. / Aman, A. / Roberts, O. / Isaac, M.B. / ...Authors: Gonzalez-Alvarez, H. / Ensan, D. / Xin, T. / Wong, J.F. / Zepeda-Velazquez, C.A. / Cros, J. / Sweeney, M.N. / Hoffer, L. / Kiyota, T. / Wilson, B.J. / Aman, A. / Roberts, O. / Isaac, M.B. / Bullock, A.N. / Smil, D. / Al-Awar, R.
History
DepositionJan 17, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 8, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 7, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond
Revision 1.2Aug 14, 2024Group: 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.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Activin receptor type I
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,91913
Polymers34,5381
Non-polymers1,38112
Water3,207178
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, Runs as a monomer in gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1740 Å2
ΔGint-64 kcal/mol
Surface area14170 Å2
Unit cell
Length a, b, c (Å)66.054, 66.054, 145.926
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221
Space group name HallP322"
Symmetry operation#1: x,y,z
#2: -y,x-y,z+2/3
#3: -x+y,-x,z+1/3
#4: x-y,-y,-z+1/3
#5: -x,-x+y,-z+2/3
#6: y,x,-z

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Components

#1: Protein Activin receptor type I


Mass: 34537.633 Da / Num. of mol.: 1 / Mutation: Q207D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACVR1 / 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-U0C / 6-methyl-9-piperazin-1-yl-4-(3,4,5-trimethoxyphenyl)-5,7-dihydropyrido[4,3-d][2]benzazepine


Mass: 460.568 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H32N4O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


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


Mass: 18.015 Da / Num. of mol.: 178 / Source method: isolated from a natural source / Formula: H2O
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: 2.66 Å3/Da / Density % sol: 53.86 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 1.6M ammonium sulfate, 0.1M tris pH 8.5, 4% glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.976254 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Sep 17, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976254 Å / Relative weight: 1
ReflectionResolution: 2.26→57.2 Å / Num. obs: 17992 / % possible obs: 100 % / Redundancy: 20.03 % / Biso Wilson estimate: 33.11 Å2 / CC1/2: 0.9883 / Rmerge(I) obs: 0.4368 / Net I/σ(I): 3.6
Reflection shellResolution: 2.26→2.3 Å / Redundancy: 20.62 % / Rmerge(I) obs: 2.1056 / Mean I/σ(I) obs: 0.54 / Num. unique obs: 874 / CC1/2: 0.8165 / % possible all: 98.76

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
xia2data reduction
DIALSdata scaling
PHASER1.20.1_4487phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3MTF

3mtf


Resolution: 2.26→57.2 Å / SU ML: 0.3373 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 25.7702
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2392 871 4.86 %
Rwork0.207 17047 -
obs0.2086 17918 99.75 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 32.59 Å2
Refinement stepCycle: LAST / Resolution: 2.26→57.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2330 0 85 178 2593
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00222481
X-RAY DIFFRACTIONf_angle_d0.56683377
X-RAY DIFFRACTIONf_chiral_restr0.0401374
X-RAY DIFFRACTIONf_plane_restr0.0035418
X-RAY DIFFRACTIONf_dihedral_angle_d15.4662346
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.26-2.40.30991480.29962761X-RAY DIFFRACTION99.39
2.4-2.590.34961400.27162797X-RAY DIFFRACTION99.76
2.59-2.850.29721380.25482801X-RAY DIFFRACTION99.59
2.85-3.260.27241380.20922828X-RAY DIFFRACTION99.9
3.26-4.10.20891620.17982856X-RAY DIFFRACTION100
4.11-57.20.18331450.17083004X-RAY DIFFRACTION99.94

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