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- PDB-8c7z: Crystal structure of the ACVR1 (ALK2) kinase in complex with the ... -

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Basic information

Entry
Database: PDB / ID: 8c7z
TitleCrystal structure of the ACVR1 (ALK2) kinase in complex with the compound M4K2308
ComponentsActivin receptor type I
KeywordsSIGNALING PROTEIN / BMP signalling Kinase Inhibitor
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 / 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
Similarity search - Domain/homology
AMMONIUM ION / Chem-TZX / Activin receptor type-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.23 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: To Be Published
Title: Crystal structure of the ACVR1 (ALK2) kinase in complex with the compound M4K2308
Authors: Cros, J. / Williams, E.P. / Sweeney, M.N. / Smil, D. / Gonzalez-Alvarez, H. / Al-awar, R. / Bullock, A.N.
History
DepositionJan 18, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 1, 2023Provider: repository / Type: Initial release
Revision 1.1Jun 19, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)36,16619
Polymers34,5381
Non-polymers1,62918
Water2,990166
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, Runs as a monomer in gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2970 Å2
ΔGint-32 kcal/mol
Surface area13610 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.280, 67.280, 140.764
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
Components on special symmetry positions
IDModelComponents
11A-737-

HOH

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Components

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Protein , 1 types, 1 molecules A

#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

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Non-polymers , 5 types, 184 molecules

#2: Chemical ChemComp-NH4 / AMMONIUM ION


Mass: 18.038 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: H4N
#3: Chemical ChemComp-TZX / 9-piperazin-1-yl-4-(3,4,5-trimethoxyphenyl)-5,6-dihydro-[1]benzoxepino[5,4-c]pyridine


Mass: 447.526 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H29N3O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-SO4 / SULFATE ION


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


Mass: 62.068 Da / Num. of mol.: 11 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 166 / 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: 2.67 Å3/Da / Density % sol: 53.9 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 1.7 M Ammonium sulphate, 0.1M tris pH 8, 8% 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 25, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976254 Å / Relative weight: 1
ReflectionResolution: 2.23→58.27 Å / Num. obs: 18645 / % possible obs: 100 % / Redundancy: 20.4 % / Biso Wilson estimate: 36.863 Å2 / CC1/2: 0.9851 / Rmerge(I) obs: 0.6976 / Net I/σ(I): 3.66
Reflection shellResolution: 2.23→2.27 Å / Redundancy: 21.3 % / Rmerge(I) obs: 4.2176 / Mean I/σ(I) obs: 0.55 / Num. unique obs: 895 / CC1/2: 0.6961 / % possible all: 99.33

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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 / Resolution: 2.23→58.27 Å / SU ML: 0.2941 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 26.2714
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2613 989 5.32 %
Rwork0.2136 17589 -
obs0.216 18578 99.82 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 36.86 Å2
Refinement stepCycle: LAST / Resolution: 2.23→58.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2305 0 103 166 2574
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00172493
X-RAY DIFFRACTIONf_angle_d0.45163379
X-RAY DIFFRACTIONf_chiral_restr0.0395373
X-RAY DIFFRACTIONf_plane_restr0.003418
X-RAY DIFFRACTIONf_dihedral_angle_d15.8187352
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.23-2.350.36831310.32782445X-RAY DIFFRACTION99.54
2.35-2.50.30551520.29652464X-RAY DIFFRACTION99.66
2.5-2.690.28771690.26912460X-RAY DIFFRACTION99.85
2.69-2.960.32721240.25012483X-RAY DIFFRACTION99.77
2.96-3.390.26821590.21142492X-RAY DIFFRACTION99.96
3.39-4.270.21031190.16362552X-RAY DIFFRACTION100
4.27-58.270.22591350.18082693X-RAY DIFFRACTION100
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)
10.191397103724-0.08574324192980.039786497850.1685072854650.1197187456270.1550666707310.03629072308190.00267248639329-0.03166103898560.0592012357798-0.07540027879450.0397539529173-0.0918419169676-0.061258551903-6.59792451226E-60.2956724234410.01524731396220.01974885143560.2992715150780.008862255469270.26267990547320.400142456-16.223087915619.5968044583
20.280725535547-0.082125915437-0.04507568362430.39430361457-0.04663458067130.4358476439170.001905754833480.0562413142104-0.0278362144425-0.02145611145110.00643438206003-0.0507332968570.0335361689578-0.03252960030135.81408507924E-70.182662383258-0.00153621719236-0.002814771224990.215317061998-0.003712099519010.18635016887930.6997561097-25.0383495664-0.307707001403
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 204 through 284 )204 - 2841 - 81
22chain 'A' and (resid 285 through 498 )285 - 49882 - 295

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