1ETR

REFINED 2.3 ANGSTROMS X-RAY CRYSTAL STRUCTURE OF BOVINE THROMBIN COMPLEXES FORMED WITH THE BENZAMIDINE AND ARGININE-BASED THROMBIN INHIBITORS NAPAP, 4-TAPAP AND MQPA: A STARTING POINT FOR IMPROVING ANTITHROMBOTICS


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Work: 0.175 
  • R-Value Observed: 0.175 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Refined 2.3 A X-ray crystal structure of bovine thrombin complexes formed with the benzamidine and arginine-based thrombin inhibitors NAPAP, 4-TAPAP and MQPA. A starting point for improving antithrombotics.

Brandstetter, H.Turk, D.Hoeffken, H.W.Grosse, D.Sturzebecher, J.Martin, P.D.Edwards, B.F.Bode, W.

(1992) J Mol Biol 226: 1085-1099

  • DOI: https://doi.org/10.1016/0022-2836(92)91054-s
  • Primary Citation of Related Structures:  
    1ETR, 1ETS, 1ETT

  • PubMed Abstract: 

    Well-diffracting crystals of bovine epsilon-thrombin in complex with several "non-peptidic" benzamidine and arginine-based thrombin inhibitors have been obtained by co-crystallization. The 2.3 A crystal structures of three complexes formed either with NAPAP, 4-TAPAP, or MQPA, were solved by Patterson search methods and refined to crystallographic R-values of 0.167 to 0.178. The active-site environment of thrombin is only slightly affected by binding of the different inhibitors; in particular, the exposed "60-insertion loop" essentially maintains its typical projecting structure. The D-stereoisomer of NAPAP and the L-stereoisomer of MQPA bind to thrombin with very similar conformations, as previously inferred from their binding to bovine trypsin; the arginine side-chain of the latter inserts into the specificity pocket in a "non-canonical" manner. The L-stereoisomer of 4-TAPAP, whose binding geometry towards trypsin was only poorly defined, is bound to the thrombin active-site in a compact conformation. In contrast to NAPAP, the distal p-amidino/guanidino groups of 4-TAPAP and MQPA do not interact with the carboxylate group of Asp189 in the thrombin specificity pocket in a "symmetrical" twin N-twin O manner, but through "lateral" single N-twin O contacts; in contrast to the p-amidino group of 4-TAPAP, however, the guanidyl group of MQPA packs favourably in the pocket due to an elaborate hydrogen bond network, which includes two entrapped water molecules. These thrombin structures confirm previous conclusions of the important role of the intermolecular hydrogen bonds formed with Gly216, and of the good sterical fit of the terminal bulky hydrophobic inhibitor groups with the hydrophobic aryl binding site and the S2-cavity, respectively, for tight thrombin active site binding of these non-peptidic inhibitors. These accurate crystal structures are presumed to be excellent starting points for the design and the elaboration of improved antithrombotics.


  • Organizational Affiliation

    Max-Planck-Institut für Biochemie, Martinsried, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
EPSILON-THROMBINA [auth L]49Bos taurusMutation(s): 0 
EC: 3.4.21.5
UniProt
Find proteins for P00735 (Bos taurus)
Explore P00735 
Go to UniProtKB:  P00735
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00735
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
EPSILON-THROMBINB [auth H]259Bos taurusMutation(s): 0 
EC: 3.4.21.5
UniProt
Find proteins for P00735 (Bos taurus)
Explore P00735 
Go to UniProtKB:  P00735
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00735
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
MIT
Query on MIT

Download Ideal Coordinates CCD File 
C [auth H]amino{[(4S)-5-[(2R,4R)-2-carboxy-4-methylpiperidin-1-yl]-4-({[(3R)-3-methyl-1,2,3,4-tetrahydroquinolin-8-yl]sulfonyl}amino)-5-oxopentyl]amino}methaniminium
C23 H37 N6 O5 S
KXNPVXPOPUZYGB-XYVMCAHJSA-O
Biologically Interesting Molecules (External Reference) 1 Unique
Entity ID: 3
IDChains NameType/Class2D Diagram3D Interactions
PRD_000452 (MIT)
Query on PRD_000452
C [auth H]ArgatrobanPeptide-like / Inhibitor
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Work: 0.175 
  • R-Value Observed: 0.175 
  • Space Group: P 42 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 87.71α = 90
b = 87.71β = 90
c = 102.98γ = 90
Software Package:
Software NamePurpose
X-PLORmodel building
X-PLORrefinement
X-PLORphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 1994-01-31
    Type: Initial release
  • Version 1.1: 2008-03-24
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Atomic model, Database references, Derived calculations, Non-polymer description, Structure summary, Version format compliance
  • Version 1.3: 2012-12-12
    Changes: Other