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- PDB-8pod: Crystal structure of the kinase domain of ACVR1 (ALK2) in complex... -

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Basic information

Entry
Database: PDB / ID: 8pod
TitleCrystal structure of the kinase domain of ACVR1 (ALK2) in complex with FKBP12 and MU1700
Components
  • Activin receptor type-1
  • Peptidyl-prolyl cis-trans isomerase FKBP1A
KeywordsSIGNALING PROTEIN / ALK2 / FKBP12 / ACVR1 / kinase / complex / inhibitor
Function / homology
Function and homology information


endocardial cushion cell fate commitment / mitral valve morphogenesis / BMP receptor complex / macrolide binding / cardiac muscle cell fate commitment / atrial septum primum morphogenesis / BMP receptor activity / endocardial cushion fusion / activin receptor binding / positive regulation of cardiac epithelial to mesenchymal transition ...endocardial cushion cell fate commitment / mitral valve morphogenesis / BMP receptor complex / macrolide binding / cardiac muscle cell fate commitment / atrial septum primum morphogenesis / BMP receptor activity / endocardial cushion fusion / activin receptor binding / 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 / regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion / cytoplasmic side of membrane / activin receptor complex / transforming growth factor beta receptor binding / activin receptor activity, type I / endocardial cushion formation / receptor protein serine/threonine kinase / transmembrane receptor protein serine/threonine kinase activity / pharyngeal system development / TGFBR1 LBD Mutants in Cancer / activin binding / cellular response to BMP stimulus / type I transforming growth factor beta receptor binding / negative regulation of activin receptor signaling pathway / activin receptor signaling pathway / heart trabecula formation / embryonic heart tube morphogenesis / gastrulation with mouth forming second / I-SMAD binding / dorsal/ventral pattern formation / transforming growth factor beta binding / regulation of amyloid precursor protein catabolic process / terminal cisterna / ryanodine receptor complex / determination of left/right symmetry / signaling receptor inhibitor activity / neural crest cell migration / atrioventricular valve morphogenesis / 'de novo' protein folding / ventricular cardiac muscle tissue morphogenesis / branching involved in blood vessel morphogenesis / ventricular septum morphogenesis / FK506 binding / negative regulation of G1/S transition of mitotic cell cycle / SMAD binding / germ cell development / TGF-beta receptor signaling activates SMADs / peptide hormone binding / mTORC1-mediated signalling / regulation of ryanodine-sensitive calcium-release channel activity / positive regulation of intracellular signal transduction / mesoderm formation / Calcineurin activates NFAT / positive regulation of SMAD protein signal transduction / regulation of ossification / regulation of immune response / BMP signaling pathway / positive regulation of bone mineralization / positive regulation of osteoblast differentiation / negative regulation of signal transduction / heart morphogenesis / supramolecular fiber organization / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / sarcoplasmic reticulum membrane / transforming growth factor beta receptor signaling pathway / protein tyrosine kinase binding / T cell activation / protein maturation / sarcoplasmic reticulum / negative regulation of extrinsic apoptotic signaling pathway / calcium channel regulator activity / peptidylprolyl isomerase / peptidyl-prolyl cis-trans isomerase activity / negative regulation of transforming growth factor beta receptor signaling pathway / cellular response to growth factor stimulus / SARS-CoV-1 activates/modulates innate immune responses / Z disc / osteoblast differentiation / apical part of cell / protein folding / regulation of protein localization / heart development / protein refolding / amyloid fibril formation / in utero embryonic development / Potential therapeutics for SARS / transmembrane transporter binding / cell differentiation / positive regulation of canonical NF-kappaB signal transduction / 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
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 / FKBP-type peptidyl-prolyl cis-trans isomerase ...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 / FKBP-type peptidyl-prolyl cis-trans isomerase / FKBP-type peptidyl-prolyl cis-trans isomerase domain / FKBP-type peptidyl-prolyl cis-trans isomerase domain profile. / Peptidyl-prolyl cis-trans isomerase domain 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
: / FLUORIDE ION / Peptidyl-prolyl cis-trans isomerase FKBP1A / Activin receptor type-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.59 Å
AuthorsCros, J. / Baltanas-Copado, J. / Knapp, S. / Paruch, K. / Nemec, N. / Bullock, A.N.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Innovative Medicines Initiative Switzerland
CitationJournal: To Be Published
Title: Crystal structure of the kinase domain of ACVR1 (ALK2) in complex with FKBP12 and MU1700
Authors: Cros, J. / Baltanas-Copado, J. / Bullock, A.N.
History
DepositionJul 4, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 19, 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: Peptidyl-prolyl cis-trans isomerase FKBP1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,8794
Polymers49,4542
Non-polymers4252
Water1,36976
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1750 Å2
ΔGint-7 kcal/mol
Surface area18680 Å2
MethodPISA
Unit cell
Length a, b, c (Å)43.343, 76.622, 138.544
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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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: 37398.746 Da / Num. of mol.: 1
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: Protein Peptidyl-prolyl cis-trans isomerase FKBP1A / PPIase FKBP1A / 12 kDa FK506-binding protein / 12 kDa FKBP / FKBP-12 / Calstabin-1 / FK506-binding ...PPIase FKBP1A / 12 kDa FK506-binding protein / 12 kDa FKBP / FKBP-12 / Calstabin-1 / FK506-binding protein 1A / FKBP-1A / Immunophilin FKBP12 / Rotamase


Mass: 12054.782 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FKBP1A, FKBP1, FKBP12 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P62942, peptidylprolyl isomerase
#3: Chemical ChemComp-7IO / 6-(4-piperazin-1-ylphenyl)-3-quinolin-4-yl-furo[3,2-b]pyridine


Mass: 406.479 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H22N4O / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-F / FLUORIDE ION


Mass: 18.998 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: F
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 76 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.33 Å3/Da / Density % sol: 47.12 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 20% PEG3350, 10% ethylene glycol, 0.1M bis-tris-propane pH 7.5, 0.2M sodium fluoride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.92272 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Dec 2, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92272 Å / Relative weight: 1
ReflectionResolution: 2.59→51.39 Å / Num. obs: 14991 / % possible obs: 99.91 % / Redundancy: 13.38 % / Biso Wilson estimate: 40.66 Å2 / CC1/2: 0.9714 / Net I/σ(I): 3.09
Reflection shellResolution: 2.59→2.63 Å / Redundancy: 14.34 % / Num. unique obs: 724 / CC1/2: 0.5912 / % possible all: 99.86

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
xia2data reduction
DIALSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.59→51.39 Å / SU ML: 0.3515 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 24.8553
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2553 751 5.03 %
Rwork0.2353 14185 -
obs0.2363 14936 99.53 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 43.41 Å2
Refinement stepCycle: LAST / Resolution: 2.59→51.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3233 0 32 76 3341
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00223340
X-RAY DIFFRACTIONf_angle_d0.45964548
X-RAY DIFFRACTIONf_chiral_restr0.0402514
X-RAY DIFFRACTIONf_plane_restr0.0042580
X-RAY DIFFRACTIONf_dihedral_angle_d5.4837468
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.59-2.790.37421410.33652753X-RAY DIFFRACTION99.25
2.79-3.070.36391410.32042804X-RAY DIFFRACTION99.49
3.07-3.510.29581420.25792814X-RAY DIFFRACTION99.46
3.52-4.430.22861530.19952847X-RAY DIFFRACTION99.7
4.43-51.390.19351740.18972967X-RAY DIFFRACTION99.75
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)
11.040594325481.14069667468-0.09372782150411.67563067942-0.3422292028521.49599538808-0.12539326646-0.490507092241-0.22626629854-0.1662477014630.3942736812570.7883676004630.120855182535-0.19306714485-0.1619753671160.285584194435-0.0872812192067-0.02617233995440.546935565076-0.03046086867270.30273620174615.6699326808-17.98484057776.85461504293
21.05976754532-0.388229110452-0.3608167586221.303239464880.3712204186520.7907242826760.0793280230403-0.2011059103230.00461734978388-0.138674513789-0.183065110432-0.0179397979839-0.02463940767380.1799717707080.01367087337340.2160395619290.0205404608905-0.05519948955610.3132015388640.02978653772070.33940564805828.5544858351-10.39072791171.27031151158
31.1166703504-0.1819224411240.3487466300961.44919382896-0.1596809616232.51465100598-0.0824165843987-0.07493876198230.050428307980.185457838189-0.0713877839807-0.110519441741-0.1027201227720.03618716019290.1753247155970.240142160527-0.0171989178718-0.05253114322410.2828456252860.05029503444360.32089783591923.0086112866-2.96731060172-3.10759339773
41.125492602390.3186498288120.1121219759421.279456827261.03399107611.13087827162-0.112631646136-0.125465754909-0.2088334376530.0363882490452-0.0292069541180.3830956781040.137152782374-0.08460808921670.09783208877470.3728738857570.0340384199881-0.07732783338350.2662424578730.01703153069260.36240841543611.32229049123.65345154558-9.26308098369
50.596304158288-0.00580058713991-0.228420880371.528119513590.6729023956741.22766662891-0.06749964666480.08801092706630.145146702781-0.122236681563-0.000613733568555-0.00517849374008-0.2600884996920.03591258392930.068773158390.2938463264130.00447228209082-0.03434968308810.2698625775420.05571327001550.3192593706218.448347277410.3280327835-17.5574202147
62.939870859-0.743368552206-0.8402297963620.7350169940190.4125327912981.2280650691-0.709095219255-0.49766858941-0.5572932799120.2883505553830.1929776566490.2026405228760.008663108235980.09693823778050.3935982708630.7145155927470.1938667127470.2030717526580.4943850726580.1723374964580.44304369044623.6402507096-19.024129960731.7475286878
71.7053652367-0.524185237416-0.004146581581251.67512209015-0.4708115432010.898766458452-0.34850556533-0.1673943739850.2687368343330.196874703820.3801863568940.1806475909850.142243464118-0.132274948333-0.04892540814610.3909483362730.07316384991520.04577285177830.4718253464080.05028452235110.39397718082417.907298465-11.806148462819.9876019969
81.6796335631-0.793221704552-0.4907221265793.66216598349-1.090885137025.24684356733-0.362578117643-0.02993154376750.1929572998560.478501284795-0.325207831342-0.562961428154-0.409642042625-0.203001676010.7034978904930.587797855666-0.0324362281961-0.04429388568460.4931808788490.01123310273010.26603729797327.8988760551-13.01463988726.4496354385
91.0539049626-0.514104923563-0.2232555393690.534201784626-0.5400478076361.54522705721-0.402850474621-0.3515989903680.01460912881020.5645661212760.243151375348-0.154982332497-0.4291153844490.005607957410290.1663507008070.4854748493110.126161310423-0.0346496627080.384211504906-0.02344432305170.33568564695722.2387565683-7.8397244394324.3784619576
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 171 through 197 )AA171 - 1971 - 21
22chain 'A' and (resid 198 through 238 )AA198 - 23822 - 62
33chain 'A' and (resid 239 through 301 )AA239 - 30163 - 124
44chain 'A' and (resid 302 through 338 )AA302 - 338125 - 161
55chain 'A' and (resid 339 through 498 )AA339 - 498162 - 321
66chain 'B' and (resid 2 through 21 )BD2 - 211 - 20
77chain 'B' and (resid 22 through 57 )BD22 - 5721 - 56
88chain 'B' and (resid 58 through 66 )BD58 - 6657 - 65
99chain 'B' and (resid 67 through 108 )BD67 - 10866 - 107

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