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- PDB-8epk: Complex of anticoagulant RNA aptamer and human coagulation factor... -

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Basic information

Entry
Database: PDB / ID: 8epk
TitleComplex of anticoagulant RNA aptamer and human coagulation factor IXa (S195A)
Components
  • (Coagulation factor IXa ...) x 2
  • RNA (31-MER)
KeywordsBLOOD CLOTTING / coagulation factor IX / RNA aptamer / inhibitor
Function / homology
Function and homology information


Defective F9 secretion / coagulation factor IXa / Defective gamma-carboxylation of F9 / Defective F9 activation / Defective factor IX causes thrombophilia / Defective cofactor function of FVIIIa variant / Defective F9 variant does not activate FX / zymogen activation / Extrinsic Pathway of Fibrin Clot Formation / Protein hydroxylation ...Defective F9 secretion / coagulation factor IXa / Defective gamma-carboxylation of F9 / Defective F9 activation / Defective factor IX causes thrombophilia / Defective cofactor function of FVIIIa variant / Defective F9 variant does not activate FX / zymogen activation / Extrinsic Pathway of Fibrin Clot Formation / Protein hydroxylation / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / Gamma-carboxylation of protein precursors / Removal of aminoterminal propeptides from gamma-carboxylated proteins / Intrinsic Pathway of Fibrin Clot Formation / Golgi lumen / blood coagulation / : / endopeptidase activity / endoplasmic reticulum lumen / serine-type endopeptidase activity / calcium ion binding / proteolysis / extracellular space / extracellular exosome / extracellular region / metal ion binding / plasma membrane
Similarity search - Function
Peptidase S1A, coagulation factor VII/IX/X/C/Z / : / Coagulation factor-like, Gla domain superfamily / Coagulation Factor Xa inhibitory site / EGF-like domain / EGF-type aspartate/asparagine hydroxylation site / EGF-like calcium-binding, conserved site / Calcium-binding EGF-like domain signature. / Aspartic acid and asparagine hydroxylation site. / EGF-like calcium-binding domain ...Peptidase S1A, coagulation factor VII/IX/X/C/Z / : / Coagulation factor-like, Gla domain superfamily / Coagulation Factor Xa inhibitory site / EGF-like domain / EGF-type aspartate/asparagine hydroxylation site / EGF-like calcium-binding, conserved site / Calcium-binding EGF-like domain signature. / Aspartic acid and asparagine hydroxylation site. / EGF-like calcium-binding domain / Calcium-binding EGF-like domain / Vitamin K-dependent carboxylation/gamma-carboxyglutamic (GLA) domain / Gamma-carboxyglutamic acid-rich (GLA) domain / Gamma-carboxyglutamic acid-rich (GLA) domain superfamily / Vitamin K-dependent carboxylation domain. / Gla domain profile. / Domain containing Gla (gamma-carboxyglutamate) residues. / Epidermal growth factor-like domain. / EGF-like domain profile. / EGF-like domain signature 1. / EGF-like domain signature 2. / EGF-like domain / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Serine proteases, trypsin family, histidine active site. / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, serine active site. / Serine proteases, trypsin domain profile. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
RNA / RNA (> 10) / Coagulation factor IX
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.65 Å
AuthorsKolyadko, V.N. / Krishnaswamy, S.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)P01HL139420 United States
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2024
Title: An RNA aptamer exploits exosite-dependent allostery to achieve specific inhibition of coagulation factor IXa.
Authors: Kolyadko, V.N. / Layzer, J.M. / Perry, K. / Sullenger, B.A. / Krishnaswamy, S.
History
DepositionOct 5, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 3, 2024Provider: repository / Type: Initial release
Revision 1.1Jul 24, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Nov 13, 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: Coagulation factor IXa light chain
B: Coagulation factor IXa heavy chain
C: Coagulation factor IXa light chain
D: Coagulation factor IXa heavy chain
E: RNA (31-MER)
F: RNA (31-MER)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)87,25410
Polymers87,1256
Non-polymers1294
Water18010
1
A: Coagulation factor IXa light chain
B: Coagulation factor IXa heavy chain
E: RNA (31-MER)
hetero molecules


  • defined by author
  • Evidence: surface plasmon resonance, Binding of coagulation factor IXa to biotinylated RNA 31-mer was confirmed with bio-layer interferometry using Octet SAX pins. Binding also confirmed by ...Evidence: surface plasmon resonance, Binding of coagulation factor IXa to biotinylated RNA 31-mer was confirmed with bio-layer interferometry using Octet SAX pins. Binding also confirmed by competition assay with heparin-Sepharose column chromatography
  • 43.6 kDa, 3 polymers
  • Search similar-shape structures of this assembly by Omokage search (details)
Theoretical massNumber of molelcules
Total (without water)43,6275
Polymers43,5623
Non-polymers642
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: Coagulation factor IXa light chain
D: Coagulation factor IXa heavy chain
F: RNA (31-MER)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,6275
Polymers43,5623
Non-polymers642
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)72.496, 79.579, 84.317
Angle α, β, γ (deg.)90.000, 101.780, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Coagulation factor IXa ... , 2 types, 4 molecules ACBD

#1: Protein Coagulation factor IXa light chain


Mass: 7267.338 Da / Num. of mol.: 2 / Fragment: furin cleavage site (RRKR) inserted
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F9 / Plasmid: phCMV1-WPRE / Details (production host): propeptide of mouse IgG HC / Cell (production host): fibroblast / Cell line (production host): AV12 / Production host: Mesocricetus auratus (golden hamster) / References: UniProt: P00740
#2: Protein Coagulation factor IXa heavy chain


Mass: 26174.818 Da / Num. of mol.: 2 / Mutation: S195A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F9 / Plasmid: phCMV1-WPRE / Details (production host): propeptide of mouse IgG HC / Cell (production host): fibroblast / Cell line (production host): AV12 / Production host: Mesocricetus auratus (golden hamster) / References: UniProt: P00740

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RNA chain , 1 types, 2 molecules EF

#3: RNA chain RNA (31-MER)


Mass: 10120.267 Da / Num. of mol.: 2
Fragment: 30 RNA residues with 2'-F and 2'-OMe modifications, capped with 5'-hexylamino linker and 3'-inverted deoxy-Thymidine residue (3'-3' linkage)
Source method: obtained synthetically / Details: Chemically synthesized / Source: (synth.) synthetic construct (others)

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Non-polymers , 3 types, 14 molecules

#4: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 10 / Source method: isolated from a natural source / Formula: H2O

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Details

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

Crystal
IDDensity Matthews (Å3/Da)Density % sol (%)Description
6_b4_cr4_1_12.73254.99plate or ribbon
1
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop
Details: 60 mM Na Citrate pH 5.0; 4% Tacsimate pH 7.0; 23% PEG 8000
PH range: 5.5 - 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 7, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.65→60.24 Å / Num. obs: 27106 / % possible obs: 98.5 % / Redundancy: 3.5 % / CC1/2: 0.997 / Rmerge(I) obs: 0.108 / Rpim(I) all: 0.068 / Rrim(I) all: 0.128 / Net I/σ(I): 8.2
Reflection shell

Diffraction-ID: 4

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2.65-2.773.62.2935060.3841.3952.68796.4
8.78-60.243.40.0327820.9980.020.03897.4

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation2.65 Å60.24 Å
Translation2.65 Å60.24 Å

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Processing

Software
NameVersionClassificationNB
REFMAC5.8.0267refinement
XDSdata reduction
Aimless0.5.32data scaling
PHASER2.8.3phasing
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 8EPH, 3DD2

8eph

3dd2


Resolution: 2.65→60.24 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.94 / SU B: 51.51 / SU ML: 0.427 / SU R Cruickshank DPI: 1.1256 / Cross valid method: THROUGHOUT / ESU R: 1.126 / ESU R Free: 0.342 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : RESIDUAL ONLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2607 1313 4.9 %RANDOM
Rwork0.2313 ---
obs0.2328 25317 96.58 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1 Å / Solvent model: MASK
Displacement parametersBiso max: 171.79 Å2 / Biso mean: 93.716 Å2 / Biso min: 48.39 Å2
Baniso -1Baniso -2Baniso -3
1-0.79 Å2-0 Å2-0.05 Å2
2---2.16 Å20 Å2
3---1.28 Å2
Refinement stepCycle: final / Resolution: 2.65→60.24 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4512 1344 4 10 5870
Biso mean--107.18 71.91 -
Num. residues----642
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0186152
X-RAY DIFFRACTIONr_bond_other_d0.0010.025026
X-RAY DIFFRACTIONr_angle_refined_deg1.7592.0968540
X-RAY DIFFRACTIONr_angle_other_deg1.1832.77411626
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0745576
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.26622.759232
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.15615772
X-RAY DIFFRACTIONr_dihedral_angle_4_deg10.5361524
X-RAY DIFFRACTIONr_chiral_restr0.1110.2934
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.025984
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021392
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.65→2.715 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.383 81 -
Rwork0.421 1548 -
obs--80.17 %
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)
12.7036-1.7869-3.27124.06590.80718.02190.2117-0.08580.158-0.45830.3875-0.3856-0.52240.583-0.59910.7821-0.05560.09780.4904-0.03940.1518-9.19119.143-58.026
22.5176-0.6461-1.27935.4723-0.51715.0494-0.0158-0.40440.1170.6847-0.0223-0.2175-0.49180.25470.0380.8707-0.00740.01190.4851-0.04210.0176-12.94210.187-33.574
30.26460.204-0.89884.62122.265910.5897-0.1415-0.1443-0.02060.77170.2222-0.06591.32610.3305-0.08071.47790.13440.040.69310.05390.148-20.762-24.5139.738
42.2742-0.06250.46385.86480.63965.5877-0.12660.1689-0.18620.054-0.0023-0.68950.74680.52840.12891.02960.1060.05450.4625-0.02420.1115-15.247-15.565-14.2
54.6742-4.32492.13885.795-0.89784.12590.21040.48140.1055-0.6765-0.3344-0.55630.46131.03150.1241.07680.20630.19310.73950.1230.17310.475-11.187-46.218
66.07582.5983-1.41875.7292-0.77745.14280.1518-0.3670.02490.6375-0.1228-0.5334-0.32440.7394-0.0291.0734-0.0204-0.1150.5608-0.08670.0795-11.6747.2182.091
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A84 - 138
2X-RAY DIFFRACTION2B16 - 245
3X-RAY DIFFRACTION3C84 - 138
4X-RAY DIFFRACTION4D16 - 245
5X-RAY DIFFRACTION5E1 - 30
6X-RAY DIFFRACTION6F1 - 30

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