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- PDB-4dym: Crystal structure of the ACVR1 kinase domain in complex with the ... -

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Basic information

Entry
Database: PDB / ID: 4dym
TitleCrystal structure of the ACVR1 kinase domain in complex with the imidazo[1,2-b]pyridazine inhibitor K00135
ComponentsActivin receptor type-1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Structural Genomics / Structural Genomics Consortium / SGC / Protein Kinase / TRANSFERASE-TRANSFERASE 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 / peptide hormone binding / positive regulation of SMAD protein signal transduction / 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-IYZ / Activin receptor type-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.42 Å
AuthorsChaikuad, A. / Sanvitale, C. / Cooper, C. / Canning, P. / Mahajan, P. / Daga, N. / Petrie, K. / Alfano, I. / Gileadi, O. / Fedorov, O. ...Chaikuad, A. / Sanvitale, C. / Cooper, C. / Canning, P. / Mahajan, P. / Daga, N. / Petrie, K. / Alfano, I. / Gileadi, O. / Fedorov, O. / Krojer, T. / Filippakopoulos, P. / Muniz, J.R.C. / von Delft, F. / Weigelt, J. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Bullock, A. / Structural Genomics Consortium (SGC)
CitationJournal: To be Published
Title: Crystal structure of the ACVR1 kinase domain in complex with the imidazo[1,2-b]pyridazine inhibitor K00135
Authors: Chaikuad, A. / Sanvitale, C. / Cooper, C. / Canning, P. / Mahajan, P. / Daga, N. / Petrie, K. / Alfano, I. / Gileadi, O. / Fedorov, O. / Krojer, T. / Filippakopoulos, P. / Muniz, J.R.C. / ...Authors: Chaikuad, A. / Sanvitale, C. / Cooper, C. / Canning, P. / Mahajan, P. / Daga, N. / Petrie, K. / Alfano, I. / Gileadi, O. / Fedorov, O. / Krojer, T. / Filippakopoulos, P. / Muniz, J.R.C. / von Delft, F. / Weigelt, J. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Bullock, A. / Structural Genomics Consortium (SGC)
History
DepositionFeb 29, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 21, 2012Provider: repository / Type: Initial release
Revision 1.1Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)35,3988
Polymers34,5321
Non-polymers8677
Water2,234124
1
A: Activin receptor type-1
hetero molecules

A: Activin receptor type-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,79716
Polymers69,0632
Non-polymers1,73414
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_555-x,y,-z+1/21
Buried area5550 Å2
ΔGint-79 kcal/mol
Surface area25770 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.800, 81.860, 140.390
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-506-

GOL

21A-704-

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.: 1 / Fragment: unp residues 299-401 / Mutation: R206H
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACVR1, ACVRLK2 / Plasmid: pFB-LIC-Bse / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q04771, receptor protein serine/threonine kinase
#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-IYZ / 1-(3-{6-[(CYCLOPROPYLMETHYL)AMINO]IMIDAZO[1,2-B]PYRIDAZIN-3-YL}PHENYL)ETHANONE / IMIDAZOPYRIDAZIN 1


Mass: 306.362 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H18N4O
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 124 / 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: 2.4 Å3/Da / Density % sol: 48.85 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 1.60M MgSO4; 0.1M MES pH 6.5, VAPOR DIFFUSION, SITTING DROP, temperature 293.15K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.9795 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Feb 4, 2010 / Details: Kirkpatrick Baez bimorph mirror pair
RadiationMonochromator: Si (111) double crystal monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.42→44.73 Å / Num. all: 13074 / Num. obs: 13046 / % possible obs: 99.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 4.5 % / Biso Wilson estimate: 37.5 Å2 / Rmerge(I) obs: 0.146 / Net I/σ(I): 8.1
Reflection shellResolution: 2.42→2.55 Å / Redundancy: 4.7 % / Rmerge(I) obs: 0.75 / Mean I/σ(I) obs: 2 / Num. unique all: 1858 / % possible all: 100

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Processing

Software
NameVersionClassification
GDAdata collection
PHASERphasing
REFMAC5.6.0117refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 3h9r

3h9r


Resolution: 2.42→39.18 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.9 / SU B: 22.958 / SU ML: 0.28 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 2 / ESU R: 0.548 / ESU R Free: 0.309 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27922 671 5.1 %RANDOM
Rwork0.21952 ---
all0.271 13046 --
obs0.22268 12375 99.66 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 35.896 Å2
Baniso -1Baniso -2Baniso -3
1--2.53 Å20 Å20 Å2
2--6.58 Å20 Å2
3----4.05 Å2
Refine analyzeLuzzati coordinate error obs: 0.233 Å
Refinement stepCycle: LAST / Resolution: 2.42→39.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2306 0 57 124 2487
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.022413
X-RAY DIFFRACTIONr_bond_other_d0.0010.021603
X-RAY DIFFRACTIONr_angle_refined_deg1.4671.9683278
X-RAY DIFFRACTIONr_angle_other_deg0.7933.0013886
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.8375292
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.71323.883103
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.15815396
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.5821514
X-RAY DIFFRACTIONr_chiral_restr0.1230.2371
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212642
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02487
LS refinement shellResolution: 2.42→2.483 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.439 33 -
Rwork0.298 849 -
obs--100 %
Refinement TLS params.Method: refined / Origin x: -15.8484 Å / Origin y: -16.5914 Å / Origin z: 17.6326 Å
111213212223313233
T0.1582 Å20.0262 Å20.0028 Å2-0.1164 Å2-0.0194 Å2--0.1506 Å2
L2.5704 °2-0.956 °20.582 °2-1.9489 °2-0.7299 °2--4.5204 °2
S-0.0873 Å °-0.2503 Å °0.0607 Å °0.0924 Å °0.1038 Å °-0.0622 Å °-0.1947 Å °-0.6744 Å °-0.0165 Å °

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