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- PDB-7c3g: Crystal structure of human ALK2 kinase domain with R206H mutation... -

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Basic information

Entry
Database: PDB / ID: 7c3g
TitleCrystal structure of human ALK2 kinase domain with R206H mutation in complex with a bicyclic pyrazole inhibitor RK-73134
ComponentsActivin receptor type-1
KeywordsSIGNALING PROTEIN / kinase / inhibitor complex
Function / homology
Function and homology information


endocardial cushion cell fate commitment / mitral valve morphogenesis / BMP receptor complex / cardiac muscle cell fate commitment / BMP receptor activity / atrial septum primum morphogenesis / endocardial cushion fusion / positive regulation of cardiac epithelial to mesenchymal transition / acute inflammatory response / positive regulation of determination of dorsal identity ...endocardial cushion cell fate commitment / mitral valve morphogenesis / BMP receptor complex / cardiac muscle cell fate commitment / BMP receptor activity / atrial septum primum morphogenesis / endocardial cushion fusion / positive regulation of cardiac epithelial to mesenchymal transition / acute inflammatory response / positive regulation of determination of dorsal identity / transforming growth factor beta receptor activity, type I / smooth muscle cell differentiation / activin receptor complex / activin receptor activity, type I / endocardial cushion formation / pharyngeal system development / transmembrane receptor protein serine/threonine kinase activity / receptor protein serine/threonine kinase / activin binding / cellular response to BMP stimulus / activin receptor signaling pathway / negative regulation of activin receptor signaling pathway / embryonic heart tube morphogenesis / gastrulation with mouth forming second / dorsal/ventral pattern formation / transforming growth factor beta binding / determination of left/right symmetry / atrioventricular valve morphogenesis / neural crest cell migration / branching involved in blood vessel morphogenesis / ventricular septum morphogenesis / negative regulation of G1/S transition of mitotic cell cycle / SMAD binding / germ cell development / peptide hormone binding / positive regulation of intracellular signal transduction / mesoderm formation / positive regulation of SMAD protein signal transduction / regulation of ossification / positive regulation of bone mineralization / positive regulation of osteoblast differentiation / negative regulation of signal transduction / BMP signaling pathway / transforming growth factor beta receptor signaling pathway / protein tyrosine kinase binding / negative regulation of extrinsic apoptotic signaling pathway / cellular response to growth factor stimulus / apical part of cell / osteoblast differentiation / heart development / in utero embryonic development / cell differentiation / 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 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. ...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 / 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
Similarity search - Domain/homology
Chem-FH0 / Activin receptor type-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.802 Å
AuthorsSakai, N. / Mishima-Tsumagari, C. / Matsumoto, T. / Shirouzu, M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2021
Title: Novel bicyclic pyrazoles as potent ALK2 (R206H) inhibitors for the treatment of fibrodysplasia ossificans progressiva.
Authors: Yamamoto, H. / Sakai, N. / Ohte, S. / Sato, T. / Sekimata, K. / Matsumoto, T. / Nakamura, K. / Watanabe, H. / Mishima-Tsumagari, C. / Tanaka, A. / Hashizume, Y. / Honma, T. / Katagiri, T. / ...Authors: Yamamoto, H. / Sakai, N. / Ohte, S. / Sato, T. / Sekimata, K. / Matsumoto, T. / Nakamura, K. / Watanabe, H. / Mishima-Tsumagari, C. / Tanaka, A. / Hashizume, Y. / Honma, T. / Katagiri, T. / Miyazono, K. / Tomoda, H. / Shirouzu, M. / Koyama, H.
History
DepositionMay 12, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 3, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 10, 2021Group: Database references / Category: citation / Item: _citation.journal_volume
Revision 1.2Nov 29, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: atom_type / chem_comp_atom ...atom_type / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z ..._atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z / _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-1
B: Activin receptor type-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,88225
Polymers69,0632
Non-polymers2,81823
Water8,449469
1
A: Activin receptor type-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,98913
Polymers34,5321
Non-polymers1,45712
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area500 Å2
ΔGint-36 kcal/mol
Surface area13320 Å2
MethodPISA
2
B: Activin receptor type-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,89312
Polymers34,5321
Non-polymers1,36111
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)84.340, 140.259, 59.758
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Components on special symmetry positions
IDModelComponents
11B-769-

HOH

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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
Details: N-terminal 2 residues "SM" are the residual of the purification tag after cleaving off the tag by protease, followed by the Q201 of ALK2
Source: (gene. exp.) Homo sapiens (human) / Gene: ACVR1, ACVRLK2 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q04771, receptor protein serine/threonine kinase
#2: Chemical ChemComp-FH0 / ~{N}-[4-(4-methylpiperazin-1-yl)phenyl]-4-(2-pyridin-3-yl-6,7-dihydro-4~{H}-pyrazolo[5,1-c][1,4]oxazin-3-yl)pyrimidin-2-amine


Mass: 468.554 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H28N8O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 17 / 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.: 469 / 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: 2.56 Å3/Da / Density % sol: 51.9 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 100 mM HEPES pH 7.6-8.0, 1.5-1.6 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: 1.8→50 Å / Num. obs: 66091 / % possible obs: 99.7 % / Redundancy: 13.39 % / Biso Wilson estimate: 34.77 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.107 / Rrim(I) all: 0.111 / Net I/σ(I): 18.92
Reflection shellResolution: 1.8→1.91 Å / Redundancy: 13.5 % / Rmerge(I) obs: 1.562 / Mean I/σ(I) obs: 1.6 / Num. unique obs: 10488 / CC1/2: 0.787 / Rrim(I) all: 1.622 / % possible all: 99.1

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Processing

Software
NameVersionClassification
REFMAC5.8.0257refinement
XDSdata reduction
XDSdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3MTF

3mtf


Resolution: 1.802→46.098 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.946 / SU B: 7.048 / SU ML: 0.108 / Cross valid method: FREE R-VALUE / ESU R: 0.122 / ESU R Free: 0.121
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2266 3302 4.997 %
Rwork0.1851 62783 -
all0.187 --
obs-66085 99.622 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 32.697 Å2
Baniso -1Baniso -2Baniso -3
1-1.837 Å20 Å20 Å2
2---2.251 Å20 Å2
3---0.414 Å2
Refinement stepCycle: LAST / Resolution: 1.802→46.098 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4680 0 171 469 5320
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0134960
X-RAY DIFFRACTIONr_bond_other_d0.0010.0174528
X-RAY DIFFRACTIONr_angle_refined_deg1.841.6496737
X-RAY DIFFRACTIONr_angle_other_deg1.4361.58510473
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.2425586
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.79822.048249
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.37815840
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.5471532
X-RAY DIFFRACTIONr_chiral_restr0.0920.2628
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.025393
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021047
X-RAY DIFFRACTIONr_nbd_refined0.2120.21043
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1860.24282
X-RAY DIFFRACTIONr_nbtor_refined0.1730.22387
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0870.22232
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1630.2371
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1160.215
X-RAY DIFFRACTIONr_nbd_other0.1810.257
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1730.224
X-RAY DIFFRACTIONr_mcbond_it1.9242.3242344
X-RAY DIFFRACTIONr_mcbond_other1.9212.3232343
X-RAY DIFFRACTIONr_mcangle_it2.9143.4672921
X-RAY DIFFRACTIONr_mcangle_other2.9143.4682922
X-RAY DIFFRACTIONr_scbond_it2.7922.7652616
X-RAY DIFFRACTIONr_scbond_other2.4412.6472561
X-RAY DIFFRACTIONr_scangle_it4.2044.033813
X-RAY DIFFRACTIONr_scangle_other3.8933.8573734
X-RAY DIFFRACTIONr_lrange_it7.65628.7175814
X-RAY DIFFRACTIONr_lrange_other7.28228.0365711
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.802-1.8490.3342370.3464532X-RAY DIFFRACTION98.4314
1.849-1.8990.3212330.34429X-RAY DIFFRACTION99.1915
1.899-1.9540.2872290.2694355X-RAY DIFFRACTION99.3068
1.954-2.0140.2552200.2364188X-RAY DIFFRACTION99.4809
2.014-2.080.2752150.2184091X-RAY DIFFRACTION99.5607
2.08-2.1530.2642110.2033995X-RAY DIFFRACTION99.6682
2.153-2.2340.2382000.1883809X-RAY DIFFRACTION99.7264
2.234-2.3250.2251940.1833696X-RAY DIFFRACTION99.8204
2.325-2.4280.2531860.1743547X-RAY DIFFRACTION99.8395
2.428-2.5460.2331800.1723407X-RAY DIFFRACTION99.8886
2.546-2.6840.2241720.1743259X-RAY DIFFRACTION99.9417
2.684-2.8460.2551620.1763092X-RAY DIFFRACTION99.9386
2.846-3.0420.2381530.182901X-RAY DIFFRACTION100
3.042-3.2850.2311430.1942705X-RAY DIFFRACTION100
3.285-3.5970.2111310.1852492X-RAY DIFFRACTION99.9619
3.597-4.0190.1871220.1652303X-RAY DIFFRACTION100
4.019-4.6350.1771060.1372030X-RAY DIFFRACTION100
4.635-5.6650.174920.1411740X-RAY DIFFRACTION100
5.665-7.960.23730.1821373X-RAY DIFFRACTION100
7.96-46.0980.238430.204839X-RAY DIFFRACTION99.7738
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)
10.27350.0485-0.1581.14810.68320.6647-0.0288-0.0555-0.0606-0.19210.0720.0386-0.16580.1241-0.04310.0938-0.05360.03860.0495-0.00790.0957-18.987118.788229.0232
20.08470.31490.04721.5987-0.1320.330.06040.04050.03320.28510.04230.22190.0210.0727-0.10270.0762-0.00180.01160.05780.00980.0881-17.754853.04861.9413
Refinement TLS group
IDRefine-IDRefine TLS-IDSelectionAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1ALLA203 - 499
2X-RAY DIFFRACTION2ALLB204 - 499

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