4DIH

X-ray structure of the complex between human alpha thrombin and thrombin binding aptamer in the presence of sodium ions


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.213 
  • R-Value Work: 0.167 
  • R-Value Observed: 0.186 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

High-resolution structures of two complexes between thrombin and thrombin-binding aptamer shed light on the role of cations in the aptamer inhibitory activity.

Russo Krauss, I.Merlino, A.Randazzo, A.Novellino, E.Mazzarella, L.Sica, F.

(2012) Nucleic Acids Res 40: 8119-8128

  • DOI: https://doi.org/10.1093/nar/gks512
  • Primary Citation of Related Structures:  
    4DIH, 4DII

  • PubMed Abstract: 

    The G-quadruplex architecture is a peculiar structure adopted by guanine-rich oligonucleotidic sequences, and, in particular, by several aptamers, including the thrombin-binding aptamer (TBA) that has the highest inhibitory activity against human α-thrombin. A crucial role in determining structure, stability and biological properties of G-quadruplexes is played by ions. In the case of TBA, K(+) ions cause an enhancement of the aptamer clotting inhibitory activity. A detailed picture of the interactions of TBA with the protein and with the ions is still lacking, despite the importance of this aptamer in biomedical field for detection and inhibition of α-thrombin. Here, we fill this gap by presenting a high-resolution crystallographic structural characterization of the thrombin-TBA complex formed in the presence of Na(+) or K(+) and a circular dichroism study of the structural stability of the aptamer both free and complexed with α-thrombin, in the presence of the two ionic species. The results indicate that the different effects exerted by Na(+) and K(+) on the inhibitory activity of TBA are related to a subtle perturbation of a few key interactions at the protein-aptamer interface. The present data, in combination with those previously obtained on the complex between α-thrombin and a modified aptamer, may allow the design of new TBA variants with a pharmacological performance enhancement.


  • Organizational Affiliation

    Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Via Cintia, I-80126 Napoli, Italia.


Macromolecules

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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ProthrombinA [auth L]36Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P00734 (Homo sapiens)
Explore P00734 
Go to UniProtKB:  P00734
PHAROS:  P00734
GTEx:  ENSG00000180210 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00734
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
ProthrombinB [auth H]259Homo sapiensMutation(s): 0 
EC: 3.4.21.5
UniProt & NIH Common Fund Data Resources
Find proteins for P00734 (Homo sapiens)
Explore P00734 
Go to UniProtKB:  P00734
PHAROS:  P00734
GTEx:  ENSG00000180210 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00734
Sequence Annotations
Expand
  • Reference Sequence

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Entity ID: 3
MoleculeChains LengthOrganismImage
Thrombin binding aptamerC [auth D]15synthetic construct
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
0G6
Query on 0G6

Download Ideal Coordinates CCD File 
E [auth H]D-phenylalanyl-N-[(2S,3S)-6-{[amino(iminio)methyl]amino}-1-chloro-2-hydroxyhexan-3-yl]-L-prolinamide
C21 H34 Cl N6 O3
DVFLYEYCMMLBTQ-VSZNYVQBSA-O
NAG
Query on NAG

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F [auth H]2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
ZN
Query on ZN

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D [auth L],
H,
I [auth H]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
CL
Query on CL

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J [auth H],
K [auth H]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
NA
Query on NA

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G [auth H],
L [auth D]
SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Biologically Interesting Molecules (External Reference) 1 Unique
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.213 
  • R-Value Work: 0.167 
  • R-Value Observed: 0.186 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 43.018α = 65.22
b = 44.716β = 85.33
c = 52.689γ = 69.97
Software Package:
Software NamePurpose
CrystalCleardata collection
CNSrefinement
HKL-2000data reduction
HKL-2000data scaling
CNSphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-07-18
    Type: Initial release
  • Version 1.1: 2012-09-26
    Changes: Database references
  • Version 1.2: 2013-02-27
    Changes: Other
  • Version 1.3: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Data collection, Derived calculations, Structure summary
  • Version 1.4: 2023-09-13
    Changes: Data collection, Database references, Refinement description, Structure summary