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- PDB-8r7g: Crystal structure of the kinase domain of ACVR1 (ALK2) with M4K2234 -

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Basic information

Entry
Database: PDB / ID: 8r7g
TitleCrystal structure of the kinase domain of ACVR1 (ALK2) with M4K2234
ComponentsActivin receptor type I
KeywordsSIGNALING PROTEIN / ALK2 / ACVR1 / kinase / inhibitor / M4K2234
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 / endocardial cushion fusion / atrial septum primum morphogenesis / 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 / endocardial cushion fusion / atrial septum primum morphogenesis / 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 / negative regulation of G1/S transition of mitotic cell cycle / ventricular septum morphogenesis / SMAD binding / germ cell development / peptide hormone binding / mesoderm formation / positive regulation of intracellular signal transduction / positive regulation of SMAD protein signal transduction / regulation of ossification / positive regulation of bone mineralization / positive regulation of osteoblast differentiation / BMP signaling pathway / 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 / 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
: / Activin receptor type-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.09 Å
AuthorsWilliams, E.P. / Cros, J. / Ensan, D. / Smil, D. / Edwards, A.M. / O'Meara, J.A. / Fernandez-Cid, A. / Isaac, M.B. / Al-awar, R. / Bullock, A.N.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Innovative Medicines Initiative Switzerland
CitationJournal: J.Med.Chem. / Year: 2020
Title: Targeting ALK2: An Open Science Approach to Developing Therapeutics for the Treatment of Diffuse Intrinsic Pontine Glioma.
Authors: Ensan, D. / Smil, D. / Zepeda-Velazquez, C.A. / Panagopoulos, D. / Wong, J.F. / Williams, E.P. / Adamson, R. / Bullock, A.N. / Kiyota, T. / Aman, A. / Roberts, O.G. / Edwards, A.M. / ...Authors: Ensan, D. / Smil, D. / Zepeda-Velazquez, C.A. / Panagopoulos, D. / Wong, J.F. / Williams, E.P. / Adamson, R. / Bullock, A.N. / Kiyota, T. / Aman, A. / Roberts, O.G. / Edwards, A.M. / O'Meara, J.A. / Isaac, M.B. / Al-Awar, R.
History
DepositionNov 24, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 3, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)140,0018
Polymers138,1514
Non-polymers1,8504
Water1,74797
1
A: Activin receptor type I
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0002
Polymers34,5381
Non-polymers4631
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Activin receptor type I
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0002
Polymers34,5381
Non-polymers4631
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Activin receptor type I
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0002
Polymers34,5381
Non-polymers4631
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Activin receptor type I
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0002
Polymers34,5381
Non-polymers4631
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)82.818, 100.594, 83.584
Angle α, β, γ (deg.)90.000, 118.130, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "A" and ((resid 206 through 209 and (name N...
d_2ens_1(chain "B" and ((resid 206 through 209 and (name N...
d_3ens_1(chain "C" and ((resid 206 through 209 and (name N...
d_4ens_1(chain "D" and ((resid 206 through 209 and (name N...

NCS domain segments:

Ens-ID: ens_1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11ARGARGGLYGLYAA206 - 2178 - 19
d_12TYRTYRLEULEUAA219 - 27921 - 81
d_13LEULEUGLNGLNAA281 - 36383 - 165
d_14VALVALILEILEAA376 - 498178 - 300
d_15234234234234AE501
d_21ARGARGGLYGLYBB206 - 2178 - 19
d_22TYRTYRARGARGBB219 - 27321 - 75
d_23SERSERLEULEUBB276 - 27978 - 81
d_24LEULEUGLNGLNBB281 - 36383 - 165
d_25VALVALILEILEBB376 - 498178 - 300
d_26234234234234BF501
d_31ARGARGARGARGCC206 - 2738 - 75
d_32SERSERLEULEUCC276 - 27978 - 81
d_33LEULEUILEILECC281 - 49883 - 300
d_34234234234234CG501
d_41ARGARGGLYGLYDD206 - 2178 - 19
d_42TYRTYRARGARGDD219 - 27321 - 75
d_43SERSERLEULEUDD276 - 27978 - 81
d_44LEULEUGLNGLNDD281 - 36383 - 165
d_45VALVALILEILEDD376 - 498178 - 300
d_46234234234234DH501

NCS oper:
IDCodeMatrixVector
1given(0.991387835916, -0.0205886185024, -0.129330072239), (-0.0183473165542, -0.999660545878, 0.0184978104173), (-0.129667014975, -0.0159656444635, -0.99142905113)-8.90100462216, -33.8525032785, -70.6556690019
2given(0.0506616253608, 0.998559823829, 0.0176544031666), (0.987617506742, -0.0474628165366, -0.149529065482), (-0.148475789586, 0.0250111831344, -0.988599706972)-27.8254381736, -19.3899578675, -100.97629614
3given(-0.0334258052967, 0.999411781898, -0.00766849032195), (-0.995336286134, -0.0325928427189, 0.0907930840345), (0.09048974, 0.0106675586265, 0.995840253328)9.56019026361, -15.9035765714, -45.2351788208

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Components

#1: Protein
Activin receptor type I


Mass: 34537.633 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACVR1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q04771, receptor protein serine/threonine kinase
#2: Chemical
ChemComp-YEE / 2-fluoranyl-6-methoxy-4-[4-methyl-5-[4-(4-propan-2-ylpiperazin-1-yl)phenyl]pyridin-3-yl]benzamide


Mass: 462.559 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H31FN4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 97 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.23 Å3/Da / Density % sol: 44.76 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 4.2 / Details: 5% PEG1000, 40% ethanol, 0.1M citrate pH 4.2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9795 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Jun 30, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.086→73.71 Å / Num. obs: 71743 / % possible obs: 99.7 % / Redundancy: 2 % / Biso Wilson estimate: 48.33 Å2 / CC1/2: 0.999 / CC star: 1 / Net I/σ(I): 11.71
Reflection shellResolution: 2.086→2.161 Å / Mean I/σ(I) obs: 0.82 / Num. unique obs: 6977 / CC1/2: 0.395

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
xia2data reduction
DIALSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.09→73.71 Å / SU ML: 0.3397 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 30.2881
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2533 3673 5.12 %
Rwork0.2267 68060 -
obs0.2281 71733 99.7 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 60.52 Å2
Refinement stepCycle: LAST / Resolution: 2.09→73.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8768 0 136 97 9001
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00499135
X-RAY DIFFRACTIONf_angle_d0.778212468
X-RAY DIFFRACTIONf_chiral_restr0.04591398
X-RAY DIFFRACTIONf_plane_restr0.00691576
X-RAY DIFFRACTIONf_dihedral_angle_d8.88891291
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AAX-RAY DIFFRACTIONTorsion NCS0.526488892745
ens_1d_3AAX-RAY DIFFRACTIONTorsion NCS1.00824586911
ens_1d_4AAX-RAY DIFFRACTIONTorsion NCS0.701995410263
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.09-2.110.3971280.36372508X-RAY DIFFRACTION96.13
2.11-2.140.32491510.35852585X-RAY DIFFRACTION98.17
2.14-2.170.38651550.34042556X-RAY DIFFRACTION99.6
2.17-2.210.37241500.352620X-RAY DIFFRACTION99.57
2.21-2.240.38451370.32232619X-RAY DIFFRACTION99.82
2.24-2.280.3361230.3182586X-RAY DIFFRACTION99.96
2.28-2.320.35331240.30772657X-RAY DIFFRACTION99.93
2.32-2.360.35051460.30162598X-RAY DIFFRACTION100
2.36-2.40.28261590.30412589X-RAY DIFFRACTION99.96
2.4-2.450.33711400.29232645X-RAY DIFFRACTION100
2.45-2.510.33161540.28112609X-RAY DIFFRACTION99.96
2.51-2.560.32521360.27182593X-RAY DIFFRACTION100
2.56-2.630.30441280.27042623X-RAY DIFFRACTION100
2.63-2.70.28931320.25932654X-RAY DIFFRACTION100
2.7-2.780.26951230.24752635X-RAY DIFFRACTION100
2.78-2.870.26151100.25092666X-RAY DIFFRACTION100
2.87-2.970.29051540.24912614X-RAY DIFFRACTION100
2.97-3.090.26371460.25242600X-RAY DIFFRACTION99.96
3.09-3.230.28151850.2572577X-RAY DIFFRACTION99.96
3.23-3.40.25881310.2372640X-RAY DIFFRACTION100
3.4-3.610.28011200.2222656X-RAY DIFFRACTION100
3.61-3.890.24641850.21412592X-RAY DIFFRACTION99.93
3.89-4.280.21141530.18212615X-RAY DIFFRACTION100
4.28-4.90.20371120.16972678X-RAY DIFFRACTION99.96
4.9-6.180.22551530.20282644X-RAY DIFFRACTION100
6.18-73.710.18611380.18982701X-RAY DIFFRACTION99.4
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)
13.021390366140.207714352709-0.2083533799141.91091134711-0.2272423420421.71913199811-0.1941421581140.4965853627740.243206186141-0.2538385050340.001064455921510.115113870262-0.04428327829790.1410325581910.1903371151290.450826478038-0.0855435194519-0.02154157927710.6430418318710.02589175510550.48941383386510.81962316734.81703393981-45.7879852079
22.441490577380.803446573791-0.1670799727982.08613144758-0.6368395575331.66659279506-0.1852897353620.66818677577-0.385586143615-0.2160173941820.211481795244-0.040620174630.1085422244870.185178870744-0.04796084482960.402056113409-0.0362350971809-0.006981650874280.467467406411-0.04849870761520.5218639458750.1036446984-4.91169005661-35.0776105654
32.118197850350.01891431823260.2799956884131.745571877890.3902651804021.8978957544-0.0218710381531-0.1509823517960.1541030796980.1316188727540.0283157100356-0.101290820755-0.1811180658950.188180739719-0.02252526876540.358316909996-0.0175204976767-0.03228494310950.3600090170170.02800109047680.422280464819-1.777570450961.84155660934-22.6267473152
42.61939521741-0.947302085659-0.6297476295741.26769708803-0.7995297719152.76548126559-0.115812740785-0.158840767868-0.043011106435-0.007759845782320.0693288366282-0.1625594522140.227549330020.4147981662230.05160510336780.3825690328160.036371009942-0.02280796071170.554230729911-0.08249261878580.4653015582677.87010095042-39.7294143676-26.7514779611
51.90988731576-0.164273479507-0.04008214397242.571488144150.5350034356452.35198775208-0.02899181366030.1264060453650.00106964946-0.2758192566070.0270813556268-0.00331731282223-0.2078659530840.1019093368620.01402461618450.365968941202-0.00679149207314-0.00100612268130.387406995109-0.03093817865930.410840493536-6.47146147833-34.0406169578-44.1985916514
62.309414871771.244194866171.603894619832.939527242620.4063114943431.838327721030.173540732339-0.3219617990830.09621070475320.207468773172-0.251287026059-0.1907838286670.0146013615977-0.08896747155360.08670179465550.66381823964-0.0695665503119-0.07038732858460.58538387706-0.02424398160980.554816359185-23.6021434581-1.40386817215-57.1497585496
71.822634010770.713980574970.2512423546844.703804358310.0228860784321.733725351210.09189359082660.0433532950292-0.125557024115-0.170342182168-0.0893098995348-0.1496564878140.1721312203240.0511940450041-0.002470344864470.429812599725-0.024168883463-0.0532150216920.3920068597540.01031589506490.386775699516-28.9774182198-17.449898091-74.4565426368
81.484405696480.445837543959-0.5499248868432.045533561110.3154158542261.926917601590.066444567053-0.0559090994111-0.107490945480.219965574294-0.199526783565-0.534189797257-0.06486369182670.07466782795810.05565652882590.5741053063850.0104727247515-0.08680543821790.4714311353640.06757170947940.62027298641713.776266759-30.6157240041-89.9308824112
92.58147961802-0.0891740525979-0.8459403362490.8912521449411.737711977283.467028214650.3858050602580.06378959806620.00231070847136-0.231249536604-0.3797493562490.0724955984337-0.776151332398-0.412201377194-0.02995060326130.7562930189260.007431460567720.003118034739250.5041799084670.02855951629130.4364117677256.93633907227-21.6437168337-81.9612842683
102.238268975590.645712896046-0.539052249961.052272478570.2952470991773.285760619340.433659627559-0.598021132518-0.3307410101330.521754089653-0.455130674516-0.384535346396-0.004797046325740.348404099851-0.03513164638870.866510401446-0.195812779614-0.1509851093330.6567510950840.1014511232370.54406761138412.8252384898-23.953066031-68.529300194
112.798211245110.589031122380.4765755387422.02961316762-1.007828137572.873365160590.150969883189-0.5755700917750.5682859332460.0748063397112-0.179787385494-0.365106901625-1.531842292810.34107810716-0.03551777145781.3829342743-0.2515399914240.1141954181250.73450838003-0.02880727749390.5752287321110.7615036284-9.62650936538-67.4106570063
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 205 through 284 )AA205 - 2841 - 78
22chain 'A' and (resid 285 through 352 )AA285 - 35279 - 146
33chain 'A' and (resid 353 through 499 )AA353 - 499147 - 293
44chain 'B' and (resid 205 through 284 )BC205 - 2841 - 79
55chain 'B' and (resid 285 through 498 )BC285 - 49880 - 293
66chain 'C' and (resid 206 through 284 )CE206 - 2841 - 78
77chain 'C' and (resid 285 through 498 )CE285 - 49879 - 280
88chain 'D' and (resid 204 through 272 )DG204 - 2721 - 69
99chain 'D' and (resid 273 through 352 )DG273 - 35270 - 149
1010chain 'D' and (resid 353 through 417 )DG353 - 417150 - 210
1111chain 'D' and (resid 418 through 498 )DG418 - 498211 - 291

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