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

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Basic information

Entry
Database: PDB / ID: 6gin
TitleCrystal structure of the ACVR1 (ALK2) kinase in complex with an Quinazolinone based ALK2 inhibitor with a 4-morpholinophenyl solvent accessible group.
ComponentsActivin receptor type-1
KeywordsSIGNALING PROTEIN / Kinase / BMP / inhibitor / signalling
Function / homology
Function and homology information


endocardial cushion cell fate commitment / mitral valve morphogenesis / BMP receptor complex / endocardial cushion fusion / 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 / BMP receptor complex / endocardial cushion fusion / 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 / activin receptor complex / transforming growth factor beta receptor activity, type I / positive regulation of determination of dorsal identity / 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 / embryonic heart tube morphogenesis / transforming growth factor beta binding / gastrulation with mouth forming second / dorsal/ventral pattern formation / determination of left/right symmetry / neural crest cell migration / atrioventricular valve morphogenesis / negative regulation of G1/S transition of mitotic cell cycle / ventricular septum morphogenesis / branching involved in blood vessel morphogenesis / SMAD binding / germ cell development / positive regulation of SMAD protein signal transduction / peptide hormone binding / mesoderm formation / regulation of ossification / BMP signaling pathway / positive regulation of osteoblast differentiation / positive regulation of bone mineralization / negative regulation of signal transduction / protein tyrosine kinase binding / transforming growth factor beta receptor signaling pathway / 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 / 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 / Transferase(Phosphotransferase) 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 / 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. / 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-IR2 / Activin receptor type-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsWilliams, E. / Hudson, L. / Bezerra, G.A. / Kopec, J. / Mahajan, P. / Kupinska, K. / Hoelder, S. / Burgess-Brown, N. / von Delft, F. / Arrowsmith, C.H. ...Williams, E. / Hudson, L. / Bezerra, G.A. / Kopec, J. / Mahajan, P. / Kupinska, K. / Hoelder, S. / Burgess-Brown, N. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Bullock, A.N.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Novel Quinazolinone Inhibitors of ALK2 Flip between Alternate Binding Modes: Structure-Activity Relationship, Structural Characterization, Kinase Profiling, and Cellular Proof of Concept.
Authors: Hudson, L. / Mui, J. / Vazquez, S. / Carvalho, D.M. / Williams, E. / Jones, C. / Bullock, A.N. / Hoelder, S.
History
DepositionMay 14, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 23, 2018Provider: repository / Type: Initial release
Revision 1.1Aug 22, 2018Group: Data collection / 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 / _citation_author.identifier_ORCID
Revision 1.2Sep 5, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Apr 3, 2019Group: Data collection / Source and taxonomy / Category: entity_src_gen / Item: _entity_src_gen.pdbx_host_org_cell_line
Revision 1.4Jan 17, 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

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Assembly

Deposited unit
A: Activin receptor type-1
B: Activin receptor type-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,76914
Polymers69,0752
Non-polymers1,69412
Water6,251347
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry, Mutation confirmed by Mass Spec.
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3280 Å2
ΔGint-85 kcal/mol
Surface area26120 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.080, 86.390, 139.290
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP22121
Space group name HallP22ab(z,x,y)
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y+1/2,-z+1/2
#4: -x,-y+1/2,z+1/2

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Components

#1: Protein Activin receptor type-1 / Activin receptor type I / ACTR-I / Activin receptor-like kinase 2 / ALK-2 / Serine/threonine- ...Activin receptor type I / ACTR-I / Activin receptor-like kinase 2 / ALK-2 / Serine/threonine-protein kinase receptor R1 / SKR1 / TGF-B superfamily receptor type I / TSR-I


Mass: 34537.633 Da / Num. of mol.: 2 / Mutation: Q207D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACVR1, ACVRLK2 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q04771, receptor protein serine/threonine kinase
#2: Chemical ChemComp-IR2 / 3-(4-morpholin-4-ylphenyl)-6-quinolin-4-yl-quinazolin-4-one


Mass: 434.489 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H22N4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 6 / 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.: 347 / Source method: isolated from a natural source / Formula: H2O

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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: 2.4 Å3/Da / Density % sol: 48.82 % / Description: P2 21 21
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 1.6M ammonium sulfate,12% glycerol, 0.1M tris pH 8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.97949 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Mar 4, 2016 / Details: Compound Refractive Lenses
RadiationMonochromator: Double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 2.2→86.39 Å / Num. obs: 36830 / % possible obs: 99.9 % / Observed criterion σ(I): 2 / Redundancy: 4.6 % / CC1/2: 0.993 / Rmerge(I) obs: 0.114 / Rpim(I) all: 0.078 / Rrim(I) all: 0.13 / Net I/σ(I): 8.8
Reflection shellResolution: 2.2→2.27 Å / Redundancy: 4.1 % / Rmerge(I) obs: 0.522 / Mean I/σ(I) obs: 2.9 / Num. unique obs: 3166 / CC1/2: 0.443 / Rpim(I) all: 0.294 / Rrim(I) all: 0.602 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX1.13-2998refinement
iMOSFLM7.2.2data reduction
Aimless7.0.044data scaling
PHASER7.0.044phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3H9R

3h9r


Resolution: 2.2→73.416 Å / Cross valid method: FREE R-VALUE / σ(F): 2 / Details: Use of TLS factors in refinement
RfactorNum. reflection% reflectionSelection details
Rfree0.2277 -5 %Random selection
Rwork0.1749 ---
obs-36830 99.7 %-
Refinement stepCycle: LAST / Resolution: 2.2→73.416 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4662 0 112 347 5121

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