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

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Basic information

Entry
Database: PDB / ID: 6acr
TitleCrystal structure of human ALK2 kinase domain with R206H mutation in complex with RK-59638
ComponentsActivin receptor type-1
KeywordsSIGNALING PROTEIN / Inhibitor / Complex / Kinase
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 / positive regulation of bone mineralization / BMP signaling pathway / 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-9TO / Activin receptor type-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.01 Å
AuthorsSakai, N. / Mishima-Tsumagari, C. / Matsumoto, T. / Shirouzu, M.
CitationJournal: Chem. Pharm. Bull. / Year: 2019
Title: Bis-Heteroaryl Pyrazoles: Identification of Orally Bioavailable Inhibitors of Activin Receptor-Like Kinase-2 (R206H).
Authors: Sekimata, K. / Sato, T. / Sakai, N. / Watanabe, H. / Mishima-Tsumagari, C. / Taguri, T. / Matsumoto, T. / Fujii, Y. / Handa, N. / Honma, T. / Tanaka, A. / Shirouzu, M. / Yokoyama, S. / ...Authors: Sekimata, K. / Sato, T. / Sakai, N. / Watanabe, H. / Mishima-Tsumagari, C. / Taguri, T. / Matsumoto, T. / Fujii, Y. / Handa, N. / Honma, T. / Tanaka, A. / Shirouzu, M. / Yokoyama, S. / Miyazono, K. / Hashizume, Y. / Koyama, H.
History
DepositionJul 27, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 20, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 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
B: Activin receptor type-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,32810
Polymers69,0632
Non-polymers1,2658
Water1,74797
1
A: Activin receptor type-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1645
Polymers34,5321
Non-polymers6334
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area210 Å2
ΔGint-18 kcal/mol
Surface area13630 Å2
MethodPISA
2
B: Activin receptor type-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1645
Polymers34,5321
Non-polymers6334
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area210 Å2
ΔGint-17 kcal/mol
Surface area13560 Å2
MethodPISA
Unit cell
Length a, b, c (Å)85.130, 138.360, 59.350
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Space group name HallP22ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x+1/2,y+1/2,-z
#4: -x,-y,z

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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: 34531.625 Da / Num. of mol.: 2 / Mutation: R206H
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-9TO / N-(4-methoxyphenyl)-4-[3-(pyridin-3-yl)-1H-pyrazol-4-yl]pyrimidin-2-amine


Mass: 344.370 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C19H16N6O
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 97 / 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: 2.6 Å3/Da / Density % sol: 52.63 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.1 M HEPES, 1.6 M Ammonium sulfate / PH range: 7.6-8.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: BL-17A / Wavelength: 0.98 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Apr 24, 2017
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 90544 / % possible obs: 99.7 % / Redundancy: 3.47 % / Biso Wilson estimate: 29.08 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.125 / Rrim(I) all: 0.147 / Net I/σ(I): 8.59
Reflection shellResolution: 2→2.13 Å / Redundancy: 3.41 % / Rmerge(I) obs: 0.946 / Mean I/σ(I) obs: 1.24 / Num. unique obs: 14636 / CC1/2: 0.621 / Rrim(I) all: 1.123 / % possible all: 99.3

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Processing

Software
NameVersionClassification
PHENIX1.13_2998+SVNrefinement
XDSVersion Nov.1 2016 BUILT=20170215data reduction
XDSVersion Nov.1 2016 BUILT=20170215data scaling
MOLREPVers 11.4.06phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3MTF

3mtf


Resolution: 2.01→45.04 Å / SU ML: 0.294 / Cross valid method: THROUGHOUT / σ(F): 1.17 / Phase error: 27.6717
RfactorNum. reflection% reflection
Rfree0.2568 4490 4.96 %
Rwork0.2131 --
obs0.2153 90502 99.68 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 33.93 Å2
Refinement stepCycle: LAST / Resolution: 2.01→45.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4724 0 82 97 4903
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00764912
X-RAY DIFFRACTIONf_angle_d0.86286661
X-RAY DIFFRACTIONf_chiral_restr0.0527734
X-RAY DIFFRACTIONf_plane_restr0.0051833
X-RAY DIFFRACTIONf_dihedral_angle_d10.2312903
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.01-2.030.37921460.3532827X-RAY DIFFRACTION97.54
2.03-2.050.3521530.32152862X-RAY DIFFRACTION99.6
2.05-2.080.34231380.31022881X-RAY DIFFRACTION99.64
2.08-2.10.33481380.29842836X-RAY DIFFRACTION99.63
2.1-2.130.34571980.29692854X-RAY DIFFRACTION99.77
2.13-2.160.3081540.28632839X-RAY DIFFRACTION99.77
2.16-2.190.30961420.28112913X-RAY DIFFRACTION99.74
2.19-2.220.34451600.27232823X-RAY DIFFRACTION99.93
2.22-2.260.32351430.25892875X-RAY DIFFRACTION99.9
2.26-2.30.31651350.2582910X-RAY DIFFRACTION99.87
2.3-2.340.27411220.25362868X-RAY DIFFRACTION99.77
2.34-2.380.33331820.26092865X-RAY DIFFRACTION99.74
2.38-2.420.27811660.25372843X-RAY DIFFRACTION99.77
2.42-2.470.27911390.24462923X-RAY DIFFRACTION99.67
2.47-2.530.31341600.23072800X-RAY DIFFRACTION99.8
2.53-2.590.27651560.22132913X-RAY DIFFRACTION100
2.59-2.650.29391640.21952835X-RAY DIFFRACTION99.87
2.65-2.720.25391550.21842859X-RAY DIFFRACTION99.83
2.72-2.80.28941240.21142935X-RAY DIFFRACTION99.93
2.8-2.890.2891920.2212786X-RAY DIFFRACTION99.87
2.89-30.29981330.23062896X-RAY DIFFRACTION99.93
3-3.120.32851310.20452895X-RAY DIFFRACTION99.74
3.12-3.260.24111420.20892889X-RAY DIFFRACTION99.93
3.26-3.430.22241520.20022840X-RAY DIFFRACTION99.87
3.43-3.640.23991340.19512894X-RAY DIFFRACTION99.87
3.64-3.920.21991370.18552907X-RAY DIFFRACTION99.84
3.92-4.320.23061260.16332878X-RAY DIFFRACTION99.64
4.32-4.940.2011600.15682869X-RAY DIFFRACTION99.34
4.94-6.230.20341330.18392856X-RAY DIFFRACTION99.73
6.23-45.060.17791750.18822841X-RAY DIFFRACTION99.24

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