1AY6

THROMBIN INHIBITOR FROM THEONALLA, CYCLOTHEANAMIDE-BASED MACROCYCLIC TRIPEPTIDE MOTIF


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Work: 0.166 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Novel thrombin inhibitors that are based on a macrocyclic tripeptide motif

Greco, M.N.Powell, E.T.Hecker, L.R.Andrade-Gordon, P.Kauffman, J.A.Lewis, J.M.Ganesh, V.Tulinsky, A.Maryanoff, B.E.

(1996) Bioorg Med Chem Lett 6: 2947-2952

  • DOI: https://doi.org/10.1073/pnas.90.17.8048
  • Primary Citation of Related Structures:  
    1AY6, 1TMB

  • PubMed Abstract: 

    The macrocyclic peptide cyclotheonamide A (CtA), isolated from the marine sponge Theonella sp., represents an unusual class of serine protease inhibitor. A complex of this inhibitor with human alpha-thrombin, a protease central to the bioregulation of thrombosis and hemostasis, was studied by x-ray crystallography. This work (2.3-A resolution) confirms the structure of CtA and reveals intimate details about its molecular recognition within the enzyme active site. Interactions due to the "Pro-Arg motif" (Arg occupancy of the S1 specificity pocket; formation of a hydrogen-bonded two-strand antiparallel beta-sheet with Ser214-Gly216) and the alpha-keto amide group of CtA are primarily responsible for binding to thrombin, with the alpha-keto amide serving as a transition-state analogue. A special interaction with the "insertion loop" of thrombin (Tyr60A-Thr60I) is manifested through engagement of the hydroxyphenyl group of CtA with Trp60D as part of an "aromatic stacking chain." Biochemical inhibition data (Ki values at 37 degrees C) were obtained for CtA with thrombin and a diverse collection of serine proteases. Thus, CtA is just a moderate inhibitor of human alpha-thrombin (Ki = 0.18 microM) but a potent inhibitor of trypsin (Ki = 0.023 microM) and streptokinase (Ki = 0.035 microM). The relative lack of potency of CtA as a thrombin inhibitor is discussed with respect to certain structural features of the enzyme complex. We also report the total synthesis of CtA, by a convergent [2 + 3] fragment-condensation approach, to serve the preparation of cyclotheonamide analogues for structure-function studies.


  • Organizational Affiliation

    Drug Discovery Division, R. W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
THROMBIN LIGHT CHAINA [auth L]36Homo 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
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
THROMBIN HEAVY CHAINB [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
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  • Reference Sequence

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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
HIRUGENC [auth I]13Hirudo medicinalisMutation(s): 0 
UniProt
Find proteins for P01050 (Hirudo medicinalis)
Explore P01050 
Go to UniProtKB:  P01050
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP01050
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1ZV
Query on 1ZV

Download Ideal Coordinates CCD File 
D [auth H]amino({3-[(3R,5R,14S,16S,21aR)-5,14-dihydroxy-1,4,17-trioxo-16-(2-phenylethyl)icosahydro-1H-pyrrolo[1,2-d][1,4,7,11]tetraazacyclononadecin-3-yl]propyl}amino)methaniminium
C30 H50 N7 O5
SNOALCJXRGNTNQ-VDKCFFHZSA-O
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
TYS
Query on TYS
C [auth I]L-PEPTIDE LINKINGC9 H11 N O6 STYR
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Work: 0.166 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 71.08α = 90
b = 72.14β = 100.8
c = 72.82γ = 90
Software Package:
Software NamePurpose
R-AXISdata collection
R-AXISdata reduction
X-PLORmodel building
PROLSQrefinement
X-PLORrefinement
R-AXISdata scaling
X-PLORphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 1998-03-18
    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
  • Version 1.4: 2023-08-02
    Changes: Database references, Derived calculations, Other, Refinement description