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

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Basic information

Entry
Database: PDB / ID: 6zgc
TitleCrystal structure of the ACVR1 (ALK2) kinase in complex with the compound Saracatinib (AZD0530)
ComponentsActivin receptor type I
KeywordsSIGNALING PROTEIN / Inhibitor complex. Kinase. Type I receptor / BMP / 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 / 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
Chem-H8H / : / PHOSPHATE ION / Activin receptor type-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.67 Å
AuthorsWilliams, E.P. / Galan Bartual, S. / Burgess-Brown, N. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Bullock, A.N.
CitationJournal: JCI Insight / Year: 2021
Title: Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva.
Authors: Williams, E. / Bagarova, J. / Kerr, G. / Xia, D.D. / Place, E.S. / Dey, D. / Shen, Y. / Bocobo, G.A. / Mohedas, A.H. / Huang, X. / Sanderson, P.E. / Lee, A. / Zheng, W. / Economides, A.N. / ...Authors: Williams, E. / Bagarova, J. / Kerr, G. / Xia, D.D. / Place, E.S. / Dey, D. / Shen, Y. / Bocobo, G.A. / Mohedas, A.H. / Huang, X. / Sanderson, P.E. / Lee, A. / Zheng, W. / Economides, A.N. / Smith, J.C. / Yu, P.B. / Bullock, A.N.
History
DepositionJun 18, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 29, 2020Provider: repository / Type: Initial release
Revision 1.1May 26, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jan 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
B: Activin receptor type I
C: Activin receptor type I
D: Activin receptor type I
hetero molecules


Theoretical massNumber of molelcules
Total (without water)141,99528
Polymers138,1514
Non-polymers3,84424
Water36020
1
A: Activin receptor type I
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4997
Polymers34,5381
Non-polymers9616
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Activin receptor type I
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4997
Polymers34,5381
Non-polymers9616
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Activin receptor type I
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4997
Polymers34,5381
Non-polymers9616
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Activin receptor type I
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4997
Polymers34,5381
Non-polymers9616
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)84.620, 101.690, 180.126
Angle α, β, γ (deg.)90.000, 95.262, 90.000
Int Tables number5
Space group name H-MI121
Space group name HallC2y(x,y,-x+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: Bound with the inhibitor Saracatinib (AZD0530) in the active site.
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-H8H / N-(5-CHLORO-1,3-BENZODIOXOL-4-YL)-7-[2-(4-METHYLPIPERAZIN-1-YL)ETHOXY]-5-(TETRAHYDRO-2H-PYRAN-4-YLOXY)QUINAZOLIN-4-AMINE / SARACATINIB


Mass: 542.026 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H32ClN5O5 / Feature type: SUBJECT OF INVESTIGATION / Comment: inhibitor*YM
#3: Chemical
ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: K
#4: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: PO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 20 / 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: 2.79 Å3/Da / Density % sol: 55.96 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.4
Details: 1.26M sodium phosphate monobasic 0.14M potassium phosphate dibasic

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.91741 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Jan 26, 2015
RadiationMonochromator: single bounce / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91741 Å / Relative weight: 1
ReflectionResolution: 2.66→44.84 Å / Num. obs: 41875 / % possible obs: 96.5 % / Redundancy: 3.3 % / Biso Wilson estimate: 57.36 Å2 / CC1/2: 0.993 / Rmerge(I) obs: 0.079 / Rpim(I) all: 0.051 / Rrim(I) all: 0.094 / Net I/σ(I): 7.8
Reflection shellResolution: 2.66→2.77 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.499 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 4448 / CC1/2: 0.79 / Rpim(I) all: 0.323 / Rrim(I) all: 0.597 / % possible all: 98.3

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
PDB_EXTRACT3.25data extraction
MOSFLM7.1.0data reduction
Aimless0.5.1data scaling
PHASER2.5.7phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3H9R

3h9r


Resolution: 2.67→44.23 Å / SU ML: 0.3806 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 29.3534
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflectionSelection details
Rfree0.2595 2096 5.01 %Random selection
Rwork0.2122 39710 --
obs0.2146 41806 96.16 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 60.89 Å2
Refinement stepCycle: LAST / Resolution: 2.67→44.23 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8988 0 236 20 9244
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00219422
X-RAY DIFFRACTIONf_angle_d0.535812850
X-RAY DIFFRACTIONf_chiral_restr0.04071457
X-RAY DIFFRACTIONf_plane_restr0.00311584
X-RAY DIFFRACTIONf_dihedral_angle_d15.21753298
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.67-2.730.33051510.29272660X-RAY DIFFRACTION97.84
2.73-2.80.35631470.27762656X-RAY DIFFRACTION97.29
2.8-2.870.34671390.28472667X-RAY DIFFRACTION97.19
2.87-2.960.33361330.26472599X-RAY DIFFRACTION95.06
2.96-3.050.33091070.25592455X-RAY DIFFRACTION89.08
3.05-3.160.30471420.26312598X-RAY DIFFRACTION94.74
3.16-3.290.31191440.26482743X-RAY DIFFRACTION98.73
3.29-3.440.28591500.24872647X-RAY DIFFRACTION98.52
3.44-3.620.28451510.22342749X-RAY DIFFRACTION98.77
3.62-3.840.26471600.20662648X-RAY DIFFRACTION97.67
3.84-4.140.27881280.18942689X-RAY DIFFRACTION97.31
4.14-4.560.18031350.17072485X-RAY DIFFRACTION90.53
4.56-5.220.21311380.17692718X-RAY DIFFRACTION97.74
5.22-6.570.24781290.20192737X-RAY DIFFRACTION97.82
6.57-44.230.22191420.18932659X-RAY DIFFRACTION94.06

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