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- PDB-3q4u: Crystal structure of the ACVR1 kinase domain in complex with LDN-... -

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Basic information

Entry
Database: PDB / ID: 3q4u
TitleCrystal structure of the ACVR1 kinase domain in complex with LDN-193189
ComponentsActivin receptor type-1
KeywordsTRANSFERASE / Structural Genomics Consortium / SGC / Protein 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 / positive regulation of SMAD protein signal transduction / peptide hormone binding / 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
CITRATE ANION / Chem-LDN / Activin receptor type-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.82 Å
AuthorsChaikuad, A. / Sanvitale, C. / Cooper, C.D.O. / Mahajan, P. / Daga, N. / Petrie, K. / Alfano, I. / Gileadi, O. / Fedorov, O. / Allerston, C.K. ...Chaikuad, A. / Sanvitale, C. / Cooper, C.D.O. / Mahajan, P. / Daga, N. / Petrie, K. / Alfano, I. / Gileadi, O. / Fedorov, O. / Allerston, C.K. / Krojer, T. / Vollmar, M. / von Delft, F. / Weigelt, J. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Bullock, A. / Structural Genomics Consortium (SGC)
CitationJournal: Plos One / Year: 2013
Title: A new class of small molecule inhibitor of BMP signaling.
Authors: Sanvitale, C.E. / Kerr, G. / Chaikuad, A. / Ramel, M.C. / Mohedas, A.H. / Reichert, S. / Wang, Y. / Triffitt, J.T. / Cuny, G.D. / Yu, P.B. / Hill, C.S. / Bullock, A.N.
History
DepositionDec 24, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 9, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Jun 18, 2014Group: Database references
Revision 1.3Sep 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

Downloads & links

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Assembly

Deposited unit
A: Activin receptor type-1
B: Activin receptor type-1
C: Activin receptor type-1
D: Activin receptor type-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)142,91534
Polymers138,1514
Non-polymers4,76430
Water18,3571019
1
A: Activin receptor type-1
B: Activin receptor type-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,45717
Polymers69,0752
Non-polymers2,38215
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4700 Å2
ΔGint10 kcal/mol
Surface area27080 Å2
2
C: Activin receptor type-1
hetero molecules

D: Activin receptor type-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,45717
Polymers69,0752
Non-polymers2,38215
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_556x,y,z+11
Buried area1730 Å2
ΔGint11 kcal/mol
Surface area14300 Å2
3
D: Activin receptor type-1
hetero molecules

C: Activin receptor type-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,45717
Polymers69,0752
Non-polymers2,38215
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_554x,y,z-11
Buried area1710 Å2
ΔGint13 kcal/mol
Surface area14630 Å2
Unit cell
Length a, b, c (Å)83.600, 98.700, 83.850
Angle α, β, γ (deg.)90.00, 117.42, 90.00
Int Tables number4
Space group name H-MP1211

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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: 34537.633 Da / Num. of mol.: 4 / Fragment: kinase domain, UNP residues 201-499 / Mutation: Q207D
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-LDN / 4-[6-(4-piperazin-1-ylphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]quinoline / LDN193189


Mass: 406.482 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C25H22N6
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical
ChemComp-FLC / CITRATE ANION / Citric acid


Mass: 189.100 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C6H5O7
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1019 / 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: 2.22 Å3/Da / Density % sol: 44.66 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / pH: 5
Details: 20% PEG 3350, 0.2M ammonium citrate dibasic pH 5.0, VAPOR DIFFUSION, SITTING DROP, temperature 293.15K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763 Å
DetectorType: ADSC Q315 3x3 CCD / Detector: CCD / Date: Jan 20, 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: 0.9763 Å / Relative weight: 1
ReflectionResolution: 1.82→41.88 Å / Num. all: 107198 / Num. obs: 107172 / % possible obs: 99.2 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 4.3 % / Biso Wilson estimate: 24.1 Å2 / Rmerge(I) obs: 0.086 / Net I/σ(I): 11.6
Reflection shellResolution: 1.82→1.92 Å / Redundancy: 4.2 % / Rmerge(I) obs: 0.734 / Mean I/σ(I) obs: 2 / Num. unique all: 15312 / % possible all: 97.8

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Processing

Software
NameVersionClassification
GDAdata collection
PHASERphasing
REFMAC5.5.0110refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb id: 3h9r chain A

3h9r


Resolution: 1.82→37.22 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.936 / SU B: 5.525 / SU ML: 0.087 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 2 / ESU R Free: 0.134 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IN REFINEMENT BUT NOT OUTPUT TO PDB
RfactorNum. reflection% reflectionSelection details
Rfree0.21863 5385 5 %RANDOM
Rwork0.16277 ---
obs0.16557 101787 99.11 %-
all-107172 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 22.583 Å2
Baniso -1Baniso -2Baniso -3
1--0.41 Å20 Å20.36 Å2
2--0.12 Å20 Å2
3---0.63 Å2
Refine analyzeLuzzati coordinate error obs: 0.19 Å
Refinement stepCycle: LAST / Resolution: 1.82→37.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9541 0 336 1019 10896
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.02210369
X-RAY DIFFRACTIONr_bond_other_d0.0010.027035
X-RAY DIFFRACTIONr_angle_refined_deg1.6471.97814124
X-RAY DIFFRACTIONr_angle_other_deg0.8673.00217040
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.15651279
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.47423.595459
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.746151782
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.0191574
X-RAY DIFFRACTIONr_chiral_restr0.1110.21554
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0211431
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022067
X-RAY DIFFRACTIONr_mcbond_it3.53336106
X-RAY DIFFRACTIONr_mcbond_other1.1232472
X-RAY DIFFRACTIONr_mcangle_it5.25759995
X-RAY DIFFRACTIONr_scbond_it7.61384263
X-RAY DIFFRACTIONr_scangle_it10.197114085
LS refinement shellResolution: 1.82→1.867 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.357 415 -
Rwork0.33 7177 -
obs--96.04 %
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)
11.3463-0.2782-0.09350.67660.21990.28410.08290.0177-0.00560.0176-0.04780.02890.00410.0326-0.03510.06380.02670.01060.0723-0.010.106920.5882-10.7836.5375
20.6389-0.03140.15680.77170.14050.18190.0647-0.0267-0.0073-0.0009-0.0611-0.0184-0.0004-0.0021-0.00360.05030.00780.00110.0823-0.01180.100539.9408-24.225810.4716
30.25070.07760.43141.56820.51551.0183-0.04870.021-0.0518-0.10210.02130.0217-0.0380.04330.02730.10460.00910.01470.0668-0.00710.091617.27029.30510.5006
40.7091-0.37030.48121.5207-0.14550.33910.05350.0694-0.01580.0584-0.0556-0.0150.0390.05190.00210.09310.0334-0.02680.093-0.01010.057523.124418.322924.0442
50.3998-0.8043-0.10813.0865-0.04250.3762-0.01090.06980.27350.2482-0.1821-0.8344-0.06760.0550.1930.04110.0012-0.08910.08770.08530.379834.574929.030424.9779
60.73680.34440.07040.32690.57721.81650.0335-0.08760.00770.0202-0.0189-0.0041-0.02020.0348-0.01460.07350.0286-0.00750.0887-0.00010.0685-3.6816-0.446931.6336
70.49160.0933-0.08110.1975-0.07410.32510.00960.0443-0.02420.0005-0.0231-0.00480.0013-0.06090.01350.06640.01490.01020.0958-0.00860.0883-12.9851-6.420810.2965
81.05270.08160.05140.3217-0.12490.7450.00730.05-0.0271-0.0256-0.0498-0.10860.06530.02720.04250.0712-0.01720.00230.0865-0.02270.089324.81894.9278-25.0957
90.3835-0.1391-0.00960.16020.03850.37090.01230.0367-0.0055-0.00090.0367-0.003-0.00510.0069-0.04910.1007-0.00180.00330.0732-0.00630.06970.9519.5304-23.7041
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A202 - 286
2X-RAY DIFFRACTION2A287 - 499
3X-RAY DIFFRACTION3B199 - 283
4X-RAY DIFFRACTION4B284 - 375
5X-RAY DIFFRACTION5B376 - 498
6X-RAY DIFFRACTION6C204 - 286
7X-RAY DIFFRACTION7C287 - 499
8X-RAY DIFFRACTION8D201 - 286
9X-RAY DIFFRACTION9D287 - 499

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