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- PDB-9d8z: Crystal structure of the ACVR1 (ALK2) Kinase Domain in complex wi... -

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Basic information

Entry
Database: PDB / ID: 9d8z
TitleCrystal structure of the ACVR1 (ALK2) Kinase Domain in complex with inhibitor CDD-2282
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: 1.85 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 20, 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)77,47514
Polymers75,4262
Non-polymers2,04912
Water4,612256
1
A: Activin receptor type-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,6436
Polymers37,7131
Non-polymers9305
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Activin receptor type-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,8338
Polymers37,7131
Non-polymers1,1197
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)52.438, 71.205, 158.979
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: 37713.160 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-A1A3D / 1-[(1r,3r)-3-(methylcarbamoyl)cyclobutyl]-N-[(1-methylpiperidin-4-yl)methyl]-2-(3,4,5-trimethoxyphenyl)-1H-1,3-benzimidazole-6-carboxamide


Mass: 549.661 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H39N5O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: PO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 256 / 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: 1.97 Å3/Da / Density % sol: 37.48 %
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: 1.85→43.77 Å / Num. obs: 51695 / % possible obs: 100 % / Redundancy: 8 % / CC1/2: 0.999 / Net I/σ(I): 13.4
Reflection shellResolution: 1.85→1.89 Å / Redundancy: 8.2 % / Num. unique obs: 3643 / CC1/2: 0.361 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX(1.21rc1_5049: ???)refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.85→43.77 Å / SU ML: 0.24 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 23.22 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2233 2000 3.87 %
Rwork0.1889 --
obs0.1902 51695 99.92 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.85→43.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4849 0 130 256 5235
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01
X-RAY DIFFRACTIONf_angle_d0.948
X-RAY DIFFRACTIONf_dihedral_angle_d18.2251894
X-RAY DIFFRACTIONf_chiral_restr0.058767
X-RAY DIFFRACTIONf_plane_restr0.009870
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.85-1.90.35341410.33733502X-RAY DIFFRACTION100
1.9-1.950.31251410.30733496X-RAY DIFFRACTION100
1.95-20.31831410.27313491X-RAY DIFFRACTION100
2-2.070.28961400.25143497X-RAY DIFFRACTION100
2.07-2.140.2531410.23743510X-RAY DIFFRACTION100
2.14-2.230.2451420.22343514X-RAY DIFFRACTION100
2.23-2.330.27321420.20333527X-RAY DIFFRACTION100
2.33-2.450.22991420.19313536X-RAY DIFFRACTION100
2.45-2.610.21241430.18823548X-RAY DIFFRACTION100
2.61-2.810.22721410.18813520X-RAY DIFFRACTION100
2.81-3.090.21961450.18623598X-RAY DIFFRACTION100
3.09-3.540.21311430.17043566X-RAY DIFFRACTION100
3.54-4.460.19011460.14593616X-RAY DIFFRACTION100
4.46-43.770.20881520.18583774X-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)
15.12291.26273.23183.7494-1.23076.40750.23630.1302-0.44880.0085-0.13440.48440.6742-0.3839-0.03390.31630.00420.0160.3877-0.14220.3089-4.2381-5.945312.9082
23.41860.664-1.22432.15230.18485.99070.10050.65840.0004-0.0894-0.03560.2662-0.0521-0.8241-0.02370.25560.0597-0.04580.4509-0.10120.3076-1.709-1.54866.581
33.46-0.09230.14252.72941.20183.65250.14310.4194-0.0945-0.19530.0717-0.4659-0.22830.2291-0.18130.2793-0.00930.03490.3309-0.04670.305117.24641.91352.326
44.7187-1.1934-0.45588.46072.47256.2932-0.2927-0.46990.08820.26990.18980.6650.1308-0.02570.09850.3073-0.01690.00680.34380.05040.2662-7.891931.638443.5001
52.9161.7402-0.81993.8035-1.30064.58130.1629-0.05020.18760.1138-0.06110.20770.0710.0391-0.05710.21460.0312-0.00170.189-0.01940.2701-1.645433.295843.3135
61.07650.2756-0.94911.9972-0.39081.5264-0.03220.2089-0.0074-0.13410.0387-0.00110.0848-0.2682-0.00920.22530.0113-0.05770.2118-0.00340.20074.878537.023632.7826
71.6279-1.5918-1.6796.37390.01872.5864-0.1385-0.84870.40571.17880.2074-1.0548-0.03260.528-0.15090.49520.063-0.17320.4772-0.06320.428516.70736.957848.1424
82.4267-0.22070.83722.69040.09393.57260.18310.2913-0.0424-0.155-0.0054-0.41310.40090.4509-0.1050.27170.07170.00740.2702-0.03150.280621.492233.551727.2342
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 203 through 254 )
2X-RAY DIFFRACTION2chain 'A' and (resid 255 through 301 )
3X-RAY DIFFRACTION3chain 'A' and (resid 302 through 499 )
4X-RAY DIFFRACTION4chain 'B' and (resid 193 through 219 )
5X-RAY DIFFRACTION5chain 'B' and (resid 220 through 273 )
6X-RAY DIFFRACTION6chain 'B' and (resid 274 through 352 )
7X-RAY DIFFRACTION7chain 'B' and (resid 353 through 376 )
8X-RAY DIFFRACTION8chain 'B' and (resid 377 through 499 )

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