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- PDB-9d8f: Crystal structure of the ACVR1 (ALK2) Kinase Domain in complex wi... -

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Basic information

Entry
Database: PDB / ID: 9d8f
TitleCrystal structure of the ACVR1 (ALK2) Kinase Domain in complex with inhibitor CDD-2281
ComponentsActivin receptor type-1
KeywordsTRANSFERASE / Kinase / ALK2 / ACVR1
Function / homology
Function and homology information


endocardial cushion cell fate commitment / mitral valve morphogenesis / BMP receptor complex / cardiac muscle cell fate commitment / 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 / smooth muscle cell differentiation ...endocardial cushion cell fate commitment / mitral valve morphogenesis / BMP receptor complex / cardiac muscle cell fate commitment / 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 / smooth muscle cell differentiation / activin receptor complex / endocardial cushion formation / transforming growth factor beta receptor activity, type I / activin receptor activity, type I / activin receptor activity, type II / BMP receptor activity / receptor protein serine/threonine kinase / transmembrane receptor protein serine/threonine kinase activity / transforming growth factor beta receptor activity, type II / pharyngeal system development / transforming growth factor beta receptor activity, type III / activin binding / cellular response to BMP stimulus / negative regulation of activin receptor signaling pathway / 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 / neural crest cell migration / atrioventricular valve morphogenesis / branching involved in blood vessel morphogenesis / ventricular septum morphogenesis / negative regulation of G1/S transition of mitotic cell cycle / SMAD binding / germ cell development / positive regulation of intracellular signal transduction / peptide hormone binding / mesoderm formation / positive regulation of SMAD protein signal transduction / regulation of ossification / BMP signaling pathway / positive regulation of bone mineralization / negative regulation of signal transduction / positive regulation of osteoblast differentiation / transforming growth factor beta receptor signaling pathway / protein tyrosine kinase binding / negative regulation of extrinsic apoptotic signaling pathway / cellular response to growth factor stimulus / osteoblast differentiation / apical part of cell / 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
: / PHOSPHATE ION / Activin receptor type-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.86 Å
AuthorsTa, H.M. / Kim, C. / Jimmidi, R. / Matzuk, M.M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)R01-HD032067 United States
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2024
Title: Discovery of highly potent and ALK2/ALK1 selective kinase inhibitors using DNA-encoded chemistry technology.
Authors: Jimmidi, R. / Monsivais, D. / Ta, H.M. / Sharma, K.L. / Bohren, K.M. / Chamakuri, S. / Liao, Z. / Li, F. / Hakenjos, J.M. / Li, J.Y. / Mishina, Y. / Pan, H. / Qin, X. / Robers, M.B. / ...Authors: Jimmidi, R. / Monsivais, D. / Ta, H.M. / Sharma, K.L. / Bohren, K.M. / Chamakuri, S. / Liao, Z. / Li, F. / Hakenjos, J.M. / Li, J.Y. / Mishina, Y. / Pan, H. / Qin, X. / Robers, M.B. / Sankaran, B. / Tan, Z. / Tang, S. / Vasquez, Y.M. / Wilkinson, J. / Young, D.W. / Palmer, S.S. / MacKenzie, K.R. / Kim, C. / Matzuk, M.M.
History
DepositionAug 19, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 27, 2024Provider: repository / Type: Initial release

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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)74,62816
Polymers72,4472
Non-polymers2,18114
Water4,630257
1
A: Activin receptor type-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,4099
Polymers36,2241
Non-polymers1,1868
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Activin receptor type-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,2197
Polymers36,2241
Non-polymers9966
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)52.663, 71.043, 158.361
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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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: 36223.590 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
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-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: PO4
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-A1A3C / N-[3-(dimethylamino)propyl]-1-[(1r,3r)-3-(methylcarbamoyl)cyclobutyl]-2-(3,4,5-trimethoxyphenyl)-1H-1,3-benzimidazole-6-carboxamide


Mass: 523.624 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H37N5O5 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 257 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.06 Å3/Da / Density % sol: 40.4 %
Crystal growTemperature: 300 K / Method: vapor diffusion, hanging drop
Details: 1.8 M sodium phosphate monobasic monohydrate, Potassium phosphate dibasic, pH 5.0.

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.97741 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 21, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97741 Å / Relative weight: 1
ReflectionResolution: 1.86→43.85 Å / Num. obs: 50819 / % possible obs: 100 % / Redundancy: 8 % / CC1/2: 0.999 / Net I/σ(I): 13.8
Reflection shellResolution: 1.86→1.91 Å / Num. unique obs: 3573 / CC1/2: 0.326 / CC star: 0.9

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Processing

Software
NameVersionClassification
PHENIX(1.21rc1_5049: ???)refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.86→43.85 Å / SU ML: 0.23 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 22.39 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2232 1999 3.93 %
Rwork0.1857 --
obs0.1872 50819 99.97 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.86→43.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4864 0 138 257 5259
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.005
X-RAY DIFFRACTIONf_angle_d0.726
X-RAY DIFFRACTIONf_dihedral_angle_d18.9141907
X-RAY DIFFRACTIONf_chiral_restr0.045769
X-RAY DIFFRACTIONf_plane_restr0.006884
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.86-1.910.38111410.32943432X-RAY DIFFRACTION100
1.91-1.960.36291410.28743444X-RAY DIFFRACTION100
1.96-2.020.27971410.25543448X-RAY DIFFRACTION100
2.02-2.080.27581400.23083412X-RAY DIFFRACTION100
2.08-2.160.25111420.21383471X-RAY DIFFRACTION100
2.16-2.240.25031400.20073419X-RAY DIFFRACTION100
2.24-2.340.2311420.18373457X-RAY DIFFRACTION100
2.34-2.470.20691420.17983461X-RAY DIFFRACTION100
2.47-2.620.22181420.17733487X-RAY DIFFRACTION100
2.62-2.820.21141430.18463486X-RAY DIFFRACTION100
2.82-3.110.21061430.17873507X-RAY DIFFRACTION100
3.11-3.560.2051450.17243518X-RAY DIFFRACTION100
3.56-4.480.1731450.1493550X-RAY DIFFRACTION100
4.48-43.850.24521520.18983728X-RAY DIFFRACTION100
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)
15.3209-0.3514-0.44436.2155-1.62267.51840.17810.56420.3147-0.16020.1321-0.7185-0.10610.2223-0.16260.34040.02050.10290.362-0.00210.296234.2487-4.0286-43.2666
22.7852-1.5557-0.94443.10521.65894.41590.12920.05640.1771-0.152-0.0357-0.15870.03210.0383-0.06770.2143-0.01430.00670.19380.04190.240228.0684-2.0072-43.0374
31.4876-0.2557-0.97471.49840.30751.585-0.0062-0.2461-0.02570.05780.03220.0430.06480.1749-0.00920.1967-0.0187-0.03730.21-0.00320.17721.41821.6224-32.7686
41.85711.5197-1.25644.147-0.14942.5567-0.01860.77850.2598-0.7940.06170.5770.1622-0.3382-0.12550.41-0.0242-0.10630.43840.03020.33989.68141.5083-48.0848
52.43320.01270.66442.6524-0.17613.19340.1504-0.2761-0.2383-0.00820.07890.41650.5666-0.3356-0.13150.264-0.0834-0.02840.27470.05770.29524.8362-4.3783-27.1122
64.71870.62730.79255.6027-0.0785.3781-0.0209-0.41280.33340.1174-0.0430.5302-0.2392-0.3931-0.03610.23280.0130.06190.2795-0.01030.29174.62479.1443-27.4808
73.8931-1.4072.53413.58761.14296.40370.0646-0.1585-0.21160.0062-0.0278-0.30480.39330.34-0.03110.2383-0.02540.03420.35450.08640.252830.7906-40.9112-13.198
83.1049-0.3272-0.79021.7403-0.38017.6763-0.0226-0.454-0.09580.01870.018-0.1210.23460.61090.05610.1856-0.0524-0.0350.3160.08910.234728.2674-37.0989-6.9346
93.29880.431-0.03572.577-0.89672.7490.1087-0.2604-0.0440.08680.03990.3989-0.1835-0.213-0.1180.2060.01680.00120.27750.03350.26698.9399-33.453-2.3583
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 193 through 219 )
2X-RAY DIFFRACTION2chain 'A' and (resid 220 through 273 )
3X-RAY DIFFRACTION3chain 'A' and (resid 274 through 352 )
4X-RAY DIFFRACTION4chain 'A' and (resid 353 through 376 )
5X-RAY DIFFRACTION5chain 'A' and (resid 377 through 477 )
6X-RAY DIFFRACTION6chain 'A' and (resid 478 through 499 )
7X-RAY DIFFRACTION7chain 'B' and (resid 200 through 254 )
8X-RAY DIFFRACTION8chain 'B' and (resid 255 through 301 )
9X-RAY DIFFRACTION9chain 'B' and (resid 302 through 499 )

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