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- PDB-6tn8: Crystal structure of the ACVR1 (ALK2) kinase in complex with the ... -

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Basic information

Entry
Database: PDB / ID: 6tn8
TitleCrystal structure of the ACVR1 (ALK2) kinase in complex with the compound BI-9564
ComponentsActivin receptor type I
KeywordsSIGNALING PROTEIN / KINASE / BMP / INHIBITOR / SIGNALLING
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-5U6 / 1,4-DIETHYLENE DIOXIDE / Activin receptor type-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.63 Å
AuthorsWilliams, E.P. / Chen, Z. / Burgess-Brown, N. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Bullock, A.N.
CitationJournal: To Be Published
Title: Crystal structure of the ACVR1 (ALK2) kinase in complex with the compound BI-9564
Authors: Williams, E.P. / Chen, Z. / Burgess-Brown, N. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Bullock, A.N.
History
DepositionDec 6, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 18, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Activin receptor type I
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,62211
Polymers34,5381
Non-polymers1,08410
Water1,58588
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, Gel filtration profile confirms monomer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1660 Å2
ΔGint-6 kcal/mol
Surface area13450 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.550, 86.540, 139.599
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Space group name HallC2c2
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z+1/2
#4: -x,-y,z+1/2
#5: x+1/2,y+1/2,z
#6: x+1/2,-y+1/2,-z
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,z+1/2

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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 / 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, 98 molecules

#2: Chemical
ChemComp-DIO / 1,4-DIETHYLENE DIOXIDE


Mass: 88.105 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C4H8O2
#3: Chemical ChemComp-5U6 / 4-[4-[(dimethylamino)methyl]-2,5-dimethoxy-phenyl]-2-methyl-2,7-naphthyridin-1-one


Mass: 353.415 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H23N3O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-SO4 / SULFATE ION


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


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 88 / 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: 2.65 Å3/Da / Density % sol: 53.57 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 1.6M ammonium sulfate, 10%(v/v) dioxane, 0.1M MES pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: May 20, 2015 / Details: Compound Refractive Lenses
RadiationMonochromator: double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.63→28.44 Å / Num. obs: 45776 / % possible obs: 99.9 % / Redundancy: 5.5 % / Biso Wilson estimate: 23.47 Å2 / CC1/2: 0.993 / Rmerge(I) obs: 0.129 / Rpim(I) all: 0.06 / Rrim(I) all: 0.143 / Net I/σ(I): 5.7
Reflection shellResolution: 1.63→1.65 Å / Redundancy: 4.1 % / Rmerge(I) obs: 1.183 / Num. unique obs: 2239 / CC1/2: 0.442 / Rpim(I) all: 0.654 / % possible all: 99

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
PHENIX1.17.1_3660refinement
iMOSFLM7.2.2.data reduction
Aimless0.5.8data scaling
PHASER2.5.7phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3H9R

3h9r


Resolution: 1.63→28.44 Å / SU ML: 0.2538 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 33.9471
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflectionSelection details
Rfree0.2624 2240 4.95 %Random selection
Rwork0.2278 42974 --
obs0.2295 45214 99.67 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 42.02 Å2
Refinement stepCycle: LAST / Resolution: 1.63→28.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2300 0 72 88 2460
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00322448
X-RAY DIFFRACTIONf_angle_d0.69293329
X-RAY DIFFRACTIONf_chiral_restr0.0442373
X-RAY DIFFRACTIONf_plane_restr0.0033415
X-RAY DIFFRACTIONf_dihedral_angle_d19.542350
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.63-1.670.51421410.49152633X-RAY DIFFRACTION99.18
1.67-1.70.47461460.4222656X-RAY DIFFRACTION99.68
1.7-1.750.40341380.38652675X-RAY DIFFRACTION99.68
1.75-1.790.33991370.3612616X-RAY DIFFRACTION99.53
1.79-1.850.38651330.32942662X-RAY DIFFRACTION99.36
1.85-1.910.30891360.29232662X-RAY DIFFRACTION99.71
1.91-1.970.28251270.27242678X-RAY DIFFRACTION99.82
1.97-2.050.29951680.24742638X-RAY DIFFRACTION99.72
2.05-2.150.30871220.2342689X-RAY DIFFRACTION99.61
2.15-2.260.24281490.22642659X-RAY DIFFRACTION99.33
2.26-2.40.27171390.22632686X-RAY DIFFRACTION99.72
2.4-2.590.31881390.22322687X-RAY DIFFRACTION99.82
2.59-2.850.24341470.22682692X-RAY DIFFRACTION99.82
2.85-3.260.24691540.22512712X-RAY DIFFRACTION99.97
3.26-4.10.23821220.18432769X-RAY DIFFRACTION100
4.1-28.440.19691420.18122860X-RAY DIFFRACTION99.77
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)
12.016608992261.30948884261-0.3978567404045.046233590143.654102341284.054903427620.03031063433680.4960665831160.2708661923690.134424166862-0.05741583994080.281813530108-0.310139494407-0.50509915705-0.01109581085450.4989696094610.240876005329-0.05378984649830.7188165422170.09741991084490.37299834228-62.0874678853202.504029256157.629957539
24.48427304131-0.169462942702-0.4317297344153.33200496552-0.2564489893923.851742719370.0198051515821-0.2841496785850.008153172463430.119820361693-0.005289743336330.253593888885-0.536610221349-0.519637827675-0.006761402309760.2107798890410.0585462639316-0.003419641561530.2874721596660.0276244744970.175517622539-54.4770588036197.870319957166.974262737
32.16928079494-0.0796415662310.02585644465550.9486143646180.6361768197814.572952559820.02906110379370.08083602058790.144554374989-0.09266552594690.04757978519360.038115267818-0.7574137119130.357885287234-0.07054318789510.281737473011-0.0788783274413-0.005200112645720.2405981431520.02101564023810.20515433769-44.3140355877198.203965314158.143684898
42.02140186969-0.09973873176710.3023411663741.316747047110.2922946650074.118701617950.09324508908820.182491627963-0.265367952257-0.09729245427860.0462997376153-0.06866554419670.3782175850861.2548313601-0.04867338819680.2171538021230.0934955236255-0.02692316435710.502218406463-0.03271708493190.263039155859-37.7530473801186.377207109154.383014601
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 204 through 229 )
2X-RAY DIFFRACTION2chain 'A' and (resid 230 through 273 )
3X-RAY DIFFRACTION3chain 'A' and (resid 274 through 338 )
4X-RAY DIFFRACTION4chain 'A' and (resid 339 through 499 )

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