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- PDB-6jux: Crystal structure of human ALK2 kinase domain with R206H mutation... -

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Basic information

Entry
Database: PDB / ID: 6jux
TitleCrystal structure of human ALK2 kinase domain with R206H mutation in complex with RK-71807
ComponentsActivin receptor type-1
KeywordsSIGNALING PROTEIN/INHIBITOR / Kinase / SIGNALING PROTEIN-INHIBITOR complex
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 / positive regulation of SMAD protein signal transduction / peptide hormone binding / 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-C9U / Activin receptor type-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.75 Å
AuthorsSakai, N. / Mishima-Tsumagari, C. / Matsumoto, T. / Shirouzu, M.
CitationJournal: Acs Omega / Year: 2020
Title: Structural Basis of Activin Receptor-Like Kinase 2 (R206H) Inhibition by Bis-heteroaryl Pyrazole-Based Inhibitors for the Treatment of Fibrodysplasia Ossificans Progressiva Identified by the ...Title: Structural Basis of Activin Receptor-Like Kinase 2 (R206H) Inhibition by Bis-heteroaryl Pyrazole-Based Inhibitors for the Treatment of Fibrodysplasia Ossificans Progressiva Identified by the Integration of Ligand-Based and Structure-Based Drug Design Approaches.
Authors: Sato, T. / Sekimata, K. / Sakai, N. / Watanabe, H. / Mishima-Tsumagari, C. / Taguri, T. / Matsumoto, T. / Fujii, Y. / Handa, N. / Tanaka, A. / Shirouzu, M. / Yokoyama, S. / Hashizume, Y. / ...Authors: Sato, T. / Sekimata, K. / Sakai, N. / Watanabe, H. / Mishima-Tsumagari, C. / Taguri, T. / Matsumoto, T. / Fujii, Y. / Handa, N. / Tanaka, A. / Shirouzu, M. / Yokoyama, S. / Hashizume, Y. / Miyazono, K. / Koyama, H. / Honma, T.
History
DepositionApr 15, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 15, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 22, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _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
Revision 1.2Nov 22, 2023Group: 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9324
Polymers34,3131
Non-polymers6193
Water3,279182
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area210 Å2
ΔGint-13 kcal/mol
Surface area13800 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.870, 86.790, 140.530
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-699-

HOH

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Components

#1: Protein Activin receptor type-1


Mass: 34313.352 Da / Num. of mol.: 1 / Fragment: UNP residues 201-499 / Mutation: R206H
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACVR1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q04771, receptor protein serine/threonine kinase
#2: Chemical ChemComp-C9U / 4-(1-ethyl-3-pyridin-3-yl-pyrazol-4-yl)-~{N}-(4-piperazin-1-ylphenyl)pyrimidin-2-amine


Mass: 426.517 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H26N8
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 182 / 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: 2.66 Å3/Da / Density % sol: 53.68 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.1 M HEPES, 1.5 M Ammonium sulfate / PH range: 7.6 - 8.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: Sep 5, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.73→48.7 Å / Num. obs: 36528 / % possible obs: 99.9 % / Redundancy: 13.33 % / Biso Wilson estimate: 37.76 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.076 / Rrim(I) all: 0.082 / Net I/σ(I): 14.61
Reflection shellResolution: 1.73→1.84 Å / Redundancy: 6.66 % / Rmerge(I) obs: 1.84 / Mean I/σ(I) obs: 1.01 / Num. unique obs: 11565 / CC1/2: 0.631 / Rrim(I) all: 1.996 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
XDSVERSION Jan 26, 2018 BUILT=20180409data reduction
XDSVERSION Jan 26, 2018 BUILT=20180409data scaling
MOLREPVers 11.6.03phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3MTF

3mtf


Resolution: 1.75→48.7 Å / Cross valid method: FREE R-VALUE
RfactorNum. reflection% reflection
Rfree0.226 1787 5 %
Rwork0.194 --
obs0.1955 34739 98.75 %
Displacement parametersBiso mean: 40.837 Å2
Refinement stepCycle: LAST / Resolution: 1.75→48.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2363 0 42 182 2587
LS refinement shellResolution: 1.75→1.8 Å /
RfactorNum. reflection
Rfree0.555 -
Rwork0.452 -
obs-2612
Refinement TLS params.Method: refined / Origin x: 15.9206 Å / Origin y: 18.6938 Å / Origin z: 17.9372 Å
111213212223313233
T0.0492 Å20.0091 Å2-0.0016 Å2-0.0275 Å20.0257 Å2--0.1207 Å2
L0.6926 °2-0.1813 °20.2925 °2-0.0551 °2-0.1907 °2--2.8327 °2
S0.0485 Å °0.0297 Å °0.0336 Å °-0.0093 Å °-0.0098 Å °0.011 Å °0.0177 Å °0.2317 Å °-0.0388 Å °

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