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141  structures 3  species 0  interactions 20  sequences 1  architecture

Family: Hirudin (PF00713)

Summary: Hirudin

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Hirudin Edit Wikipedia article

Structure of Hirudin in complex with Thrombin.[1]
Hirudine
PDB 1dwc EBI.jpg
crystallographic analysis at 3.0-angstroms resolution of the binding to human thrombin of four active site-directed inhibitors
Identifiers
Symbol Hirudin
Pfam PF00713
InterPro IPR000429
SCOP 4htc
SUPERFAMILY 4htc

Hirudin is a naturally occurring peptide in the salivary glands of medicinal leeches (such as Hirudo medicinalis) that has a blood anticoagulant property. This is fundamental for the leeches’ alimentary habit of hematophagy, since it keeps the blood flowing after the initial phlebotomy performed by the worm on the host’s skin.

Structure[edit]

During his years in Birmingham and Edinburgh, John Berry Haycraft had been actively engaged in research and published papers on the coagulation of blood, and in 1884, he discovered that the leech secreted a powerful anticoagulant, which he named hirudin, although it was not isolated until the 1950s, nor its structure fully determined until 1976. Full length hirudin is made up of 65 amino acids. These amino acids are organised into a compact N-terminal domain containing three disulfide bonds and a C-terminal domain that is completely disordered when the protein is un-complexed in solution.[2][3] Amino acid residues 1-3 form a parallel beta- strand with residues 214-217 of thrombin, the nitrogen atom of residue 1 making a hydrogen bond with the Ser-195 O gamma atom of the catalytic site. The C-terminal domain makes numerous electrostatic interactions with an anion-binding exosite of thrombin, while the last five residues are in a helical loop that forms many hydrophobic contacts.[4] Natural hirudin contains a mixture of various isoforms of the protein. However, recombinant techniques can be used to produce homogeneous preparations of hirudin.[5]

Biological activity[edit]

A key event in the final stages of blood coagulation is the conversion of fibrinogen into fibrin by the serine protease enzyme thrombin.[6] Thrombin is produced from prothrombin, by the action of an enzyme, prothrombinase (Factor Xa along with Factor Va as a cofactor), in the final states of coagulation. Fibrin is then cross linked by factor XIII (Fibrin Stabilizing Factor) to form a blood clot. The principal inhibitor of thrombin in normal blood circulation is antithrombin.[5] Similar to antithrombin III, the anticoagulatant activity of hirudin is based on its ability to inhibit the procoagulant activity of thrombin.

Hirudin is the most potent natural inhibitor of thrombin. Unlike antithrombin, hirudin binds to and inhibits only the activity of thrombin, with a specific activity on fibrinogen.[5] Therefore, hirudin prevents or dissolves the formation of clots and thrombi (i.e., it has a thrombolytic activity), and has therapeutic value in blood coagulation disorders, in the treatment of skin hematomas and of superficial varicose veins, either as an injectable or a topical application cream. In some aspects, hirudin has advantages over more commonly used anticoagulants and thrombolytics, such as heparin, as it does not interfere with the biological activity of other serum proteins, and can also act on complexed thrombin.

It is difficult to extract large amounts of hirudin from natural sources, so a method for producing and purifying this protein using recombinant biotechnology has been developed. This has led to the development and marketing of a number of hirudin-based anticoagulant pharmaceutical products, such as lepirudin (Refludan), hirudin derived from Hansenula (Thrombexx, Extrauma) and desirudin (Revasc/Iprivask). Several other direct thrombin inhibitors are derived chemically from hirudin.

See also[edit]

References[edit]

  1. ^ PDB 4HTC
  2. ^ Folkers PJM, Clore GM. et al. (1989). "Solution structure of recombinant hirudin and the Lys-47-Glu mutant: a nuclear magnetic resonance and hybrid distance geometry-dynamical simulated annealing study". Biochemistry 28 (6): 2601–2617. doi:10.1021/bi00432a038. PMID 2567183. 
  3. ^ Haruyama H. and Wuthrich K. (1989). "Conformation of recombinant desulfatohirudin in aqueous solution determined by nuclear magnetic resonance". Biochemistry 28 (10): 4301–4312. doi:10.1021/bi00436a027. PMID 2765488. 
  4. ^ Rydel TJ, Ravichandran KG, Tulinsky A, Bode W, Huber R, Roitsch C, Fenton JW (July 1990). "The structure of a complex of recombinant hirudin and human alpha-thrombin". Science 249 (4966): 277–80. doi:10.1126/science.2374926. PMID 2374926. 
  5. ^ a b c Rydell TJ, Tulinsky A. et al. (1991). "Refined structure of the Hirudin-Thrombin complex". J. Mol. Biol. 221 (2): 583–601. doi:10.1016/0022-2836(91)80074-5. PMID 1920434. 
  6. ^ Fenton JW 2nd, Ofosu SA et al. (1998). "Thrombin and antithrombotics". Semin Thromb Hemost 24 (2): 87–91. doi:10.1055/s-2007-995828. PMID 9579630. 

External links[edit]

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

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External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR000429

Peptide proteinase inhibitors can be found as single domain proteins or as single or multiple domains within proteins; these are referred to as either simple or compound inhibitors, respectively. In many cases they are synthesised as part of a larger precursor protein, either as a prepropeptide or as an N-terminal domain associated with an inactive peptidase or zymogen. This domain prevents access of the substrate to the active site. Removal of the N-terminal inhibitor domain either by interaction with a second peptidase or by autocatalytic cleavage activates the zymogen. Other inhibitors interact direct with proteinases using a simple noncovalent lock and key mechanism; while yet others use a conformational change-based trapping mechanism that depends on their structural and thermodynamic properties.

The hirudin family are proteinase inhibitors that belong to MEROPS inhibitor family I14, clan IM. Hirudin is a potent thrombin inhibitor secreted by the salivary glands of the Hirudinaria manillensis (Buffalo leech) and Hirudo medicinalis (Medicinal leech) [PUBMED:3513162]. It forms a stable non-covalent complex with alpha-thrombin, thereby abolishing its ability to cleave fibrinogen.

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Seed source: Pfam-B_707 (release 2.1)
Previous IDs: none
Type: Domain
Author: Bateman A
Number in seed: 8
Number in full: 20
Average length of the domain: 57.20 aa
Average identity of full alignment: 81 %
Average coverage of the sequence by the domain: 94.47 %

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build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 25.0 25.0
Trusted cut-off 34.7 34.7
Noise cut-off 20.3 17.5
Model length: 64
Family (HMM) version: 12
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Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Hirudin domain has been found. There are 141 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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