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- PDB-9rda: Cocrystal structure of Zilurgisertib bound to the ALK2-FKBP12 complex -

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Basic information

Entry
Database: PDB / ID: 9rda
TitleCocrystal structure of Zilurgisertib bound to the ALK2-FKBP12 complex
Components
  • Activin receptor type-1
  • Peptidyl-prolyl cis-trans isomerase FKBP1A
KeywordsTRANSFERASE / kinase / inhibitor / complex
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 / atrial septum primum morphogenesis / endocardial cushion fusion / macrolide binding / positive regulation of cardiac epithelial to mesenchymal transition / activin receptor binding ...endocardial cushion cell fate commitment / mitral valve morphogenesis / BMP receptor complex / cardiac muscle cell fate commitment / BMP receptor activity / atrial septum primum morphogenesis / endocardial cushion fusion / macrolide binding / positive regulation of cardiac epithelial to mesenchymal transition / activin receptor binding / 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 / regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion / transforming growth factor beta receptor binding / cytoplasmic side of membrane / pharyngeal system development / transmembrane receptor protein serine/threonine kinase activity / receptor protein serine/threonine kinase / activin binding / cellular response to BMP stimulus / TGFBR1 LBD Mutants in Cancer / type I transforming growth factor beta receptor binding / activin receptor signaling pathway / negative regulation of activin receptor signaling pathway / embryonic heart tube morphogenesis / heart trabecula formation / gastrulation with mouth forming second / I-SMAD binding / dorsal/ventral pattern formation / transforming growth factor beta binding / determination of left/right symmetry / regulation of amyloid precursor protein catabolic process / signaling receptor inhibitor activity / terminal cisterna / ryanodine receptor complex / atrioventricular valve morphogenesis / neural crest cell migration / 'de novo' protein folding / branching involved in blood vessel morphogenesis / ventricular cardiac muscle tissue morphogenesis / ventricular septum morphogenesis / negative regulation of G1/S transition of mitotic cell cycle / FK506 binding / SMAD binding / germ cell development / TGF-beta receptor signaling activates SMADs / peptide hormone binding / positive regulation of intracellular signal transduction / mTORC1-mediated signalling / mesoderm formation / regulation of ryanodine-sensitive calcium-release channel activity / positive regulation of SMAD protein signal transduction / Calcineurin activates NFAT / regulation of ossification / regulation of immune response / positive regulation of bone mineralization / positive regulation of osteoblast differentiation / BMP signaling pathway / negative regulation of signal transduction / heart morphogenesis / supramolecular fiber organization / sarcoplasmic reticulum membrane / transforming growth factor beta receptor signaling pathway / protein tyrosine kinase binding / T cell activation / sarcoplasmic reticulum / protein maturation / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / 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 / Z disc / apical part of cell / SARS-CoV-1 activates/modulates innate immune responses / osteoblast differentiation / protein folding / regulation of protein localization / heart development / protein refolding / in utero embryonic development / amyloid fibril formation / 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
: / Peptidyl-prolyl cis-trans isomerase FKBP1A / Activin receptor type-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.748 Å
AuthorsDekker, C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Acs Med.Chem.Lett. / Year: 2025
Title: Discovery and Characterization of Zilurgisertib, a Potent and Selective Inhibitor of Activin Receptor-like Kinase-2 (ALK2) for the Treatment of Fibrodysplasia Ossificans Progressiva
Authors: Ullrich, T. / Guth, S. / Arista, L. / Weiler, S. / Stiefl, N. / Teixeira-Fouchard, S. / Dekker, C. / Hinniger, A. / Head, V. / Kneissel, M. / Kramer, I.
History
DepositionJun 2, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 12, 2025Provider: 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)50,73517
Polymers49,3612
Non-polymers1,37415
Water7,188399
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4670 Å2
ΔGint30 kcal/mol
Surface area18940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)43.62, 108.04, 115.2
Angle α, β, γ (deg.)90, 90, 90
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: 37370.734 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACVR1, ACVRLK2 / Cell line (production host): Sf21 / 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: 11990.676 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-A1JFB / Zilurgisertib / 2-azanyl-5-[4-[(1~{R},5~{S})-3-(oxan-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl]cyclohexa-1,4-dien-1-yl]-~{N}-(4-oxidanyl-1-bicyclo[2.2.2]octanyl)pyridine-3-carboxamide


Mass: 504.664 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H40N4O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 399 / 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: 2.75 Å3/Da / Density % sol: 55.27 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7
Details: protein: reservoir 2:1 Crystallization Reservoir Solution = 0.24M Ammonium Sulphate, 0.1M Hepes pH 7.0, 28% PEG3350 Crystallization Protein Solution = Alk2-FKBP12 at 7.0 mg/ml in 50 mM Tris, ...Details: protein: reservoir 2:1 Crystallization Reservoir Solution = 0.24M Ammonium Sulphate, 0.1M Hepes pH 7.0, 28% PEG3350 Crystallization Protein Solution = Alk2-FKBP12 at 7.0 mg/ml in 50 mM Tris, 150 mM NaCl, 2 mM TCEP, pH 7.0 concentrated in the presence of 2.5 mM AMPPNP and 20 mM MgCl2 cryo condition: 10% ethyleneglycol for 2 min

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 12, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.75→78.81 Å / Num. obs: 47269 / % possible obs: 84.9 % / Redundancy: 6.5 % / CC1/2: 0.998 / Rmerge(I) obs: 0.098 / Rpim(I) all: 0.042 / Rrim(I) all: 0.107 / Net I/σ(I): 11.1
Reflection shellResolution: 1.752→1.862 Å / Rmerge(I) obs: 1.498 / Mean I/σ(I) obs: 1.4 / Num. unique obs: 2363 / CC1/2: 0.516 / Rpim(I) all: 0.621 / Rrim(I) all: 1.623 / % possible all: 25.8

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
autoPROC1.1.7data reduction
STARANISO1.10.15betadata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.748→78.81 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.942 / SU R Cruickshank DPI: 0.125 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.134 / SU Rfree Blow DPI: 0.123 / SU Rfree Cruickshank DPI: 0.118
RfactorNum. reflection% reflectionSelection details
Rfree0.2236 2291 -RANDOM
Rwork0.194 ---
obs0.1954 47269 84.4 %-
Displacement parametersBiso mean: 33.03 Å2
Baniso -1Baniso -2Baniso -3
1--0.9011 Å20 Å20 Å2
2---1.638 Å20 Å2
3---2.539 Å2
Refine analyzeLuzzati coordinate error obs: 0.25 Å
Refinement stepCycle: LAST / Resolution: 1.748→78.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3358 0 93 399 3850
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0093542HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.984780HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1222SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes583HARMONIC5
X-RAY DIFFRACTIONt_it3542HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion449SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact3278SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.75
X-RAY DIFFRACTIONt_other_torsion15.47
LS refinement shellResolution: 1.75→1.83 Å
RfactorNum. reflection% reflection
Rfree0.2965 48 -
Rwork0.2833 --
obs0.284 946 13.46 %
Refinement TLS params.

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)
10.1495-0.06220.07261.1354-0.31010.1912-0.00830.0714-0.03670.0714-0.0102-0.0238-0.0367-0.02380.0185-0.0347-0.0004-0.0075-0.02870.01230.012814.4965-6.6712-13.6902
20.605-0.4513-0.73411.2090.34080.6533-0.1956-0.07250.1806-0.07250.01660.00750.18060.00750.1791-0.0261-0.01470.0384-0.0404-0.020.009511.7925-43.4746-19.1076
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A172 - 498
2X-RAY DIFFRACTION2{ B|* }B0 - 108

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