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- PDB-8tqs: Complex of human thrombin (S195A) bound to a bivalent inhibitor c... -

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Basic information

Entry
Database: PDB / ID: 8tqs
TitleComplex of human thrombin (S195A) bound to a bivalent inhibitor comprised of DNA Aptamer HD22 conjugated to Dabigatran with a linker.
Components
  • DNA (30-MER)
  • ProthrombinThrombin
  • Thrombin heavy chain
KeywordsBLOOD CLOTTING / Human thrombin / DNA aptamer / Dabigatran
Function / homology
Function and homology information


positive regulation of lipid kinase activity / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / cytolysis by host of symbiont cells / thrombospondin receptor activity / Defective factor XII causes hereditary angioedema / thrombin / regulation of blood coagulation / ligand-gated ion channel signaling pathway / neutrophil-mediated killing of gram-negative bacterium / Defective F8 cleavage by thrombin ...positive regulation of lipid kinase activity / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / cytolysis by host of symbiont cells / thrombospondin receptor activity / Defective factor XII causes hereditary angioedema / thrombin / regulation of blood coagulation / ligand-gated ion channel signaling pathway / neutrophil-mediated killing of gram-negative bacterium / Defective F8 cleavage by thrombin / Platelet Aggregation (Plug Formation) / negative regulation of astrocyte differentiation / negative regulation of platelet activation / positive regulation of collagen biosynthetic process / negative regulation of cytokine production involved in inflammatory response / positive regulation of blood coagulation / negative regulation of fibrinolysis / Gamma-carboxylation of protein precursors / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / Common Pathway of Fibrin Clot Formation / Removal of aminoterminal propeptides from gamma-carboxylated proteins / fibrinolysis / regulation of cytosolic calcium ion concentration / Intrinsic Pathway of Fibrin Clot Formation / Peptide ligand-binding receptors / positive regulation of release of sequestered calcium ion into cytosol / Regulation of Complement cascade / acute-phase response / Cell surface interactions at the vascular wall / lipopolysaccharide binding / negative regulation of proteolysis / positive regulation of receptor signaling pathway via JAK-STAT / growth factor activity / positive regulation of insulin secretion / platelet activation / response to wounding / Golgi lumen / positive regulation of protein localization to nucleus / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / positive regulation of reactive oxygen species metabolic process / blood coagulation / antimicrobial humoral immune response mediated by antimicrobial peptide / Thrombin signalling through proteinase activated receptors (PARs) / heparin binding / regulation of cell shape / positive regulation of cell growth / G alpha (q) signalling events / collagen-containing extracellular matrix / blood microparticle / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / cell surface receptor signaling pathway / positive regulation of protein phosphorylation / G protein-coupled receptor signaling pathway / endoplasmic reticulum lumen / signaling receptor binding / serine-type endopeptidase activity / calcium ion binding / positive regulation of cell population proliferation / proteolysis / extracellular space / extracellular exosome / extracellular region / plasma membrane
Similarity search - Function
Prothrombin/thrombin / Thrombin light chain / Thrombin light chain domain superfamily / Thrombin light chain / Kringle domain / Kringle / Kringle, conserved site / Kringle superfamily / Kringle domain signature. / Kringle domain profile. ...Prothrombin/thrombin / Thrombin light chain / Thrombin light chain domain superfamily / Thrombin light chain / Kringle domain / Kringle / Kringle, conserved site / Kringle superfamily / Kringle domain signature. / Kringle domain profile. / Kringle 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. / Kringle-like fold / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, histidine active site. / Serine proteases, trypsin domain profile. / Serine proteases, trypsin family, serine active site. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
Chem-4CC / DNA / DNA (> 10) / Prothrombin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.207 Å
AuthorsKrishnaswamy, S. / Kumar, S.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL-139420 United States
CitationJournal: Nat Commun / Year: 2024
Title: Aptameric hirudins as selective and reversible EXosite-ACTive site (EXACT) inhibitors.
Authors: Yu, H. / Kumar, S. / Frederiksen, J.W. / Kolyadko, V.N. / Pitoc, G. / Layzer, J. / Yan, A. / Rempel, R. / Francis, S. / Krishnaswamy, S. / Sullenger, B.A.
History
DepositionAug 8, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 1, 2024Provider: repository / Type: Initial release
Revision 1.1May 22, 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_DOI / _citation.pdbx_database_id_PubMed / _citation.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
D: DNA (30-MER)
H: Thrombin heavy chain
L: Prothrombin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,9388
Polymers44,0033
Non-polymers9355
Water25214
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)81.626, 81.626, 190.514
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212

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Components

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DNA chain / Protein / Protein/peptide / Sugars , 4 types, 4 molecules DHL

#1: DNA chain DNA (30-MER)


Mass: 9416.036 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: HD22 aptamer with 7A extension at 5' end / Source: (synth.) Homo sapiens (human)
#2: Protein Thrombin heavy chain /


Mass: 29764.219 Da / Num. of mol.: 1 / Mutation: S195A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F2 / Production host: Homo sapiens (human) / References: UniProt: P00734
#3: Protein/peptide Prothrombin / Thrombin


Mass: 4822.365 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F2 / Production host: Homo sapiens (human) / References: UniProt: P00734
#8: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 5 types, 18 molecules

#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#6: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID / MES (buffer)


Mass: 195.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#7: Chemical ChemComp-4CC / N-[(2-{[(4-carbamimidoylphenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl]-N-pyridin-2-yl-beta-alanine / Dabigatran


Mass: 471.511 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H25N7O3 / Feature type: SUBJECT OF INVESTIGATION / Comment: anticoagulant*YM
#9: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 14 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.43 Å3/Da / Density % sol: 64.16 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 0.1 M MES monohydrate pH 6, 22% (v/v) polyethylene glycol 400 (Hampton PEGRx1 #08)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-1 / Wavelength: 0.979354 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jun 29, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979354 Å / Relative weight: 1
ReflectionResolution: 2.2→41.2 Å / Num. obs: 33265 / % possible obs: 100 % / Redundancy: 14.4 % / CC1/2: 0.99 / Rmerge(I) obs: 0.153 / Rpim(I) all: 0.042 / Rrim(I) all: 0.159 / Net I/σ(I): 8.9
Reflection shellResolution: 2.21→5.99 Å / Redundancy: 15.3 % / Rmerge(I) obs: 5.615 / Num. unique obs: 1614 / CC1/2: 0.4 / Rpim(I) all: 1.473 / Rrim(I) all: 5.808 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0419refinement
autoPROC1.0.5data scaling
XDSJan 10, 2022data reduction
PHASER2.8.2phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.207→41.138 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.947 / WRfactor Rfree: 0.244 / WRfactor Rwork: 0.213 / SU B: 20.763 / SU ML: 0.207 / Average fsc free: 0.9352 / Average fsc work: 0.9453 / Cross valid method: THROUGHOUT / ESU R: 0.196 / ESU R Free: 0.174
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflectionSelection details
Rfree0.2446 1999 6.056 %RANDOM
Rwork0.2138 31011 --
all0.216 ---
obs-33010 99.23 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.1 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 80.055 Å2
Baniso -1Baniso -2Baniso -3
1--0.805 Å20 Å20 Å2
2---0.805 Å20 Å2
3---1.61 Å2
Refinement stepCycle: LAST / Resolution: 2.207→41.138 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2371 629 63 14 3077
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0030.0123199
X-RAY DIFFRACTIONr_bond_other_d0.0010.0162670
X-RAY DIFFRACTIONr_angle_refined_deg1.0661.7114458
X-RAY DIFFRACTIONr_angle_other_deg0.3471.5946178
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7055289
X-RAY DIFFRACTIONr_dihedral_angle_2_deg4.746521
X-RAY DIFFRACTIONr_dihedral_angle_other_2_deg0.585523
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.16110426
X-RAY DIFFRACTIONr_dihedral_angle_6_deg14.25910118
X-RAY DIFFRACTIONr_chiral_restr0.0470.2462
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.023322
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02710
X-RAY DIFFRACTIONr_nbd_refined0.1930.2589
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1940.22574
X-RAY DIFFRACTIONr_nbtor_refined0.1930.21407
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.080.21475
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2560.267
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other00.21
X-RAY DIFFRACTIONr_metal_ion_refined0.0950.22
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1070.212
X-RAY DIFFRACTIONr_nbd_other0.1780.238
X-RAY DIFFRACTIONr_mcbond_it3.033.0121165
X-RAY DIFFRACTIONr_mcbond_other3.0283.0121165
X-RAY DIFFRACTIONr_mcangle_it4.395.4081451
X-RAY DIFFRACTIONr_mcangle_other4.395.4091452
X-RAY DIFFRACTIONr_scbond_it4.9943.9022034
X-RAY DIFFRACTIONr_scbond_other4.9933.9072035
X-RAY DIFFRACTIONr_scangle_it7.5766.9893007
X-RAY DIFFRACTIONr_scangle_other7.5756.9923008
X-RAY DIFFRACTIONr_lrange_it11.88638.0123782
X-RAY DIFFRACTIONr_lrange_other11.88938.0213782
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
2.207-2.2640.4891340.40720790.41224100.8090.86791.82570.408
2.264-2.3260.4011400.38321700.38423330.8830.88299.01410.381
2.326-2.3940.3561370.35121330.35122780.9160.9199.64880.347
2.394-2.4670.3471350.33220820.33322240.9160.9299.68520.323
2.467-2.5480.2691290.30820060.30521390.9460.93799.8130.289
2.548-2.6370.3191270.29219730.29321000.9240.9461000.267
2.637-2.7360.2941210.27618820.27720030.9540.9521000.243
2.736-2.8470.2981180.26618330.26819530.9430.95699.89760.229
2.847-2.9730.2921150.24117650.24418820.9560.96499.89370.208
2.973-3.1170.2761070.25216770.25417840.9480.9591000.222
3.117-3.2850.2451050.22816120.22917170.9510.9671000.205
3.285-3.4830.253980.20715320.2116300.9610.9731000.196
3.483-3.7210.258930.20314530.20615470.9540.97599.93540.198
3.721-4.0170.226860.19413330.19614190.9690.9791000.193
4.017-4.3960.187820.16812640.16913460.9790.9841000.179
4.396-4.9080.164730.15511440.15512170.980.9851000.173
4.908-5.6530.176670.17710200.17710880.980.98199.90810.204
5.653-6.8910.204560.1868870.1879430.9780.9811000.216
6.891-9.6120.285460.1897150.1947610.9480.9771000.237
9.612-41.1380.284300.2274510.2314840.970.95799.38020.287
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)
15.64522.5330.50114.86771.7265.82350.1778-0.499-1.02880.7010.1218-1.25920.86570.9431-0.29960.61750.107-0.13870.98670.07690.36326.157.35540.444
24.2285-0.7080.23772.32190.47793.25060.03140.33580.2867-0.40680.0007-0.1463-0.1270.4804-0.03210.5805-0.05210.00740.3910.03960.026-10.56817.32823.857
31.5671-1.3744-0.78183.18930.71384.49990.07660.2215-0.4366-0.2537-0.05070.45770.567-0.1964-0.0260.5437-0.0735-0.08630.3856-0.01130.1566-24.6028.72225.603
Refinement TLS groupSelection: ALL

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