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Hydrolase/hydrolase inhibitor PDB id
Protein chains
29 a.a. *
252 a.a. *
Waters ×239
* Residue conservation analysis
PDB id:
Name: Hydrolase/hydrolase inhibitor
Title: Molecular basis for the inhibition of human alpha-thrombin b macrocyclic peptide cyclotheonamide a
Structure: Alpha-thrombin (small subunit). Chain: l. Alpha-thrombin (large subunit). Chain: h. Hirugen. Chain: i. Engineered: yes. Cyclotheonamide a. Chain: t
Source: Homo sapiens. Human. Organism_taxid: 9606. Synthetic: yes. Theonella sp.. Sponges. Organism_taxid: 73791
Biol. unit: Not given
2.30Å     R-factor:   0.138    
Authors: X.Qiu,K.P.Padmanabhan,B.E.Maryanoff,A.Tulinsky
Key ref: B.E.Maryanoff et al. (1993). Molecular basis for the inhibition of human alpha-thrombin by the macrocyclic peptide cyclotheonamide A. Proc Natl Acad Sci U S A, 90, 8048-8052. PubMed id: 8367461 DOI: 10.1073/pnas.90.17.8048
27-May-93     Release date:   31-Jan-94    
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Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin
622 a.a.
29 a.a.
Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin
622 a.a.
252 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains L, H: E.C.  - Thrombin.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Preferential cleavage: Arg-|-Gly; activates fibrinogen to fibrin and releases fibrinopeptide A and B.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   1 term 
  Biological process     blood coagulation   2 terms 
  Biochemical function     catalytic activity     3 terms  


DOI no: 10.1073/pnas.90.17.8048 Proc Natl Acad Sci U S A 90:8048-8052 (1993)
PubMed id: 8367461  
Molecular basis for the inhibition of human alpha-thrombin by the macrocyclic peptide cyclotheonamide A.
B.E.Maryanoff, X.Qiu, K.P.Padmanabhan, A.Tulinsky, H.R.Almond, P.Andrade-Gordon, M.N.Greco, J.A.Kauffman, K.C.Nicolaou, A.Liu.
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 fragment-condensation approach, to serve the preparation of cyclotheonamide analogues for structure-function studies.

Literature references that cite this PDB file's key reference

  PubMed id Reference
20102178 G.G.Xu, and F.A.Etzkorn (2010).
Convergent synthesis of alpha-ketoamide inhibitors of Pin1.
  Org Lett, 12, 696-699.  
20077463 N.Schaschke, and C.P.Sommerhoff (2010).
Upgrading a Natural Product: Inhibition of Human beta-Tryptase by Cyclotheonamide Analogues.
  ChemMedChem, 5, 367-370.  
16923023 B.E.Maryanoff, D.F.McComsey, M.J.Costanzo, S.C.Yabut, T.Lu, M.R.Player, E.C.Giardino, and B.P.Damiano (2006).
Exploration of potential prodrugs of RWJ-445167, an oxyguanidine-based dual inhibitor of thrombin and factor Xa.
  Chem Biol Drug Des, 68, 29-36.  
17059471 S.Butenas, T.Orfeo, M.Kalafatis, and K.G.Mann (2006).
Peptidomimetic inhibitors for activated protein C: implications for hemophilia management.
  J Thromb Haemost, 4, 2411-2416.  
16344948 S.Cotesta, and M.Stahl (2006).
The environment of amide groups in protein-ligand complexes: H-bonds and beyond.
  J Mol Model, 12, 436-444.  
15776313 D.Sipkema, M.C.Franssen, R.Osinga, J.Tramper, and R.H.Wijffels (2005).
Marine sponges as pharmacy.
  Mar Biotechnol (NY), 7, 142-162.  
15635223 E.Toyota, H.Sekizaki, Y.U.Takahashi, K.Itoh, and K.Tanizawa (2005).
Amidino-containing Schiff base copper(II) and iron(III) chelates as a thrombin inhibitor.
  Chem Pharm Bull (Tokyo), 53, 22-26.  
10380350 A.Lombardi, G.De Simone, S.Galdiero, N.Staiano, F.Nastri, and V.Pavone (1999).
From natural to synthetic multisite thrombin inhibitors.
  Biopolymers, 51, 19-39.  
  9521099 G.De Simone, A.Lombardi, S.Galdiero, F.Nastri, R.Della Morte, N.Staiano, C.Pedone, M.Bolognesi, and V.Pavone (1998).
Hirunorms are true hirudin mimetics. The crystal structure of human alpha-thrombin-hirunorm V complex.
  Protein Sci, 7, 243-253.
PDB code: 5gds
9718968 H.Kubinyi (1998).
[Molecular similarity. 2. The structural basis of drug design]
  Pharm Unserer Zeit, 27, 158-172.  
  9792427 S.Tada, and J.J.Blow (1998).
The replication licensing system.
  Biol Chem, 379, 941-949.  
8951649 A.Caflisch (1996).
Computational combinatorial ligand design: application to human alpha-thrombin.
  J Comput Aided Mol Des, 10, 372-396.  
8786410 P.D.Grootenhuis, and M.Karplus (1996).
Functionality map analysis of the active site cleft of human thrombin.
  J Comput Aided Mol Des, 10, 1.  
  8868478 R.Krishnan, A.Tulinsky, G.P.Vlasuk, D.Pearson, P.Vallar, P.Bergum, T.K.Brunck, and W.C.Ripka (1996).
Synthesis, structure, and structure-activity relationships of divalent thrombin inhibitors containing an alpha-keto-amide transition-state mimetic.
  Protein Sci, 5, 422-433.
PDB code: 1dit
  7756983 J.Vijayalakshmi, K.P.Padmanabhan, K.G.Mann, and A.Tulinsky (1994).
The isomorphous structures of prethrombin2, hirugen-, and PPACK-thrombin: changes accompanying activation and exosite binding to thrombin.
  Protein Sci, 3, 2254-2271.
PDB codes: 1hag 1hah 1hai
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.