Semin Thromb Hemost 2006; 32: 016-031
DOI: 10.1055/s-2006-939551
Copyright © 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

The Structure of Thrombin: A Janus-Headed Proteinase

Wolfram Bode1
  • 1The Proteinase Research Group, Max-Planck-Institute of Biochemistry, Martinsried, Germany
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Publication History

Publication Date:
02 May 2006 (online)

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ABSTRACT

Through a series of successive, cascade-like proteinase activation and amplification steps, any vascular injury triggers a rapid burst of α-thrombin, a trypsin-like serine proteinase. Thrombin, the main executioner of the coagulation cascade, has procoagulant as well as anticoagulant and antifibrinolytic properties. It exhibits quite diverse physiological functions, but also gives rise to several thrombotic disorders, such as thromboembolism, myocardial infarction, and stroke, thus making it an attractive target for antithrombotic agents. Thrombin interacts specifically with several protein substrates, receptors, cofactors, inhibitors, carbohydrates, and modulators. It cleaves fibrinogen, factors XI (FXI) and FXIII, cofactors V and VIII, and the thrombin receptors; uses thrombomodulin to activate protein C and thrombin-activatable-fibrinolysis inhibitor; is inhibited by heparin cofactor II and antithrombin III with the help of acidic carbohydrates; and its activity/specificity is modulated by sodium ions. A large number of crystal structures of α-thrombin in complexes with synthetic polypeptides and protein inhibitors, substrate fragments, cofactors, and carbohydrates have displayed extended recognition sites on the thrombin surface, reflecting the versatility and multifunctional specificity of this remarkable proteinase. These structures essentially show that the thrombin surface can be subdivided into several functional regions, which recognize different chemical moieties. By using different combinations of these surface elements, thrombin can interact with a variety of molecules with high specificity, accounting for its multifunctional properties.

REFERENCES

1 Protein Data Bank [PDB] accession code 1PPB.

2 EC 3.4.21.5; MEROPS classification peptidase S01.217 of family S1A, clan PA(S).[18]

3 PDB code 1JMO.

4 PDB codes 1FPH and 1BBR.

5 PDB code 1YCP.

6 PDB code 1DE7.

7 PDB code 1BTH.

8 PDB codes 1SGI, 1SG8, 1SHH, and 1SFQ.

9 PDB code 1JOU_EF.

10 PDB code 1RD3.

11 PDB code 4HTC.

12 PDB code 1HGT.

13 PDB codes 1TBR and 1TOC.

14 PDB code 1AVG.

15 PDB code 1QVH.

16 PDB code 1UCY.

17 PDB code 1NRS.

18 PDB code 1NRN.

19 PDB code 1JMO.

20 PDB codes 1NU7 and 2A1D.

21 PDB code 1NU9.

22 PDB code 1XMN.

23 PDB code 1TB6.

24 PDB code 1SR5.

25 PDB codes 2HPQ and 2HPP.

26 PDB code 1A0H.

27 PDB code 1E0F.

28 PDB code 1DX5.

29 PDB code 1P8V and 100K.

Wolfram BodeDr. rer. nat. 

Professor, Proteinase Research Group, Max-Planck-Institute of Biochemistry, Am Klopferspitz, Martinsried, Germany

Email: bode@biochem.mpg.de