Thrombin

Coagulation factor II (thrombin)
The structure of human thrombin in complex with the inhibitor hirudin.[1]
Available structures PDB 1a2c, 1a3b, 1a3e, 1a46, 1a4w, 1a5g, 1a61, 1abi, 1abj, 1ad8, 1ae8, 1afe, 1aht, 1ai8, 1aix, 1awf, 1awh, 1ay6, 1b5g, 1b7x, 1ba8, 1bb0, 1bbr, 1bcu, 1bhx, 1bmm, 1bmn, 1bth, 1c1u, 1c1v, 1c1w, 1c4u, 1c4v, 1c4y, 1c5l, 1c5n, 1c5o, 1ca8, 1d3d, 1d3p, 1d3q, 1d3t, 1d4p, 1d6w, 1d9i, 1de7, 1dit, 1dm4, 1doj, 1dwb, 1dwc, 1dwd, 1dwe, 1dx5, 1e0f, 1eb1, 1eoj, 1eol, 1fpc, 1fph, 1g30, 1g32, 1g37, 1ghv, 1ghw, 1ghx, 1ghy, 1gj4, 1gj5, 1h8d, 1h8i, 1hag, 1hah, 1hai, 1hao, 1hap, 1hbt, 1hdt, 1hgt, 1hlt, 1hut, 1hxe, 1hxf, 1ihs, 1iht, 1jmo, 1jou, 1jwt, 1k21, 1k22, 1kts, 1ktt, 1lhc, 1lhd, 1lhe, 1lhf, 1lhg, 1mh0, 1mu6, 1mu8, 1mue, 1nm6, 1no9, 1nrn, 1nro, 1nrp, 1nrq, 1nrr, 1nrs, 1nt1, 1nu7, 1nu9, 1ny2, 1nzq, 1o0d, 1o2g, 1o5g, 1ook, 1oyt, 1p8v, 1ppb, 1qbv, 1qhr, 1qj1, 1qj6, 1qj7, 1qur, 1rd3, 1riw, 1sb1, 1sfq, 1sg8, 1sgi, 1shh, 1sl3, 1sr5, 1t4u, 1t4v, 1ta2, 1ta6, 1tb6, 1tbz, 1thp, 1thr, 1ths, 1tmb, 1tmt, 1tmu, 1tom, 1tq0, 1tq7, 1twx, 1ucy, 1uma, 1uvs, 1vit, 1vr1, 1vzq, 1w7g, 1way, 1wbg, 1xm1, 1xmn, 1ycp, 1ype, 1ypg, 1ypj, 1ypk, 1ypl, 1ypm, 1z71, 1z8i, 1z8j, 1zgi, 1zgv, 1zrb, 2a0q, 2a2x, 2a45, 2afq, 2ank, 2anm, 2b5t, 2bdy, 2bvr, 2bvs, 2bvx, 2bxt, 2bxu, 2c8w, 2c8x, 2c8y, 2c8z, 2c90, 2c93, 2cf8, 2cf9, 2cn0, 2feq, 2fes, 2gde, 2gp9, 2h9t, 2hgt, 2hnt, 2hpp, 2hpq, 2hwl, 2jh0, 2jh5, 2jh6, 2od3, 2thf, 3hat, 3htc, 4htc, 4thn, 5gds, 7kme, 8kme
Identifiers
Symbols	F2; PT
External IDs	OMIM: 176930 MGI: 88380 HomoloGene: 426 GeneCards: F2 Gene
EC number	3.4.21.5
Gene Ontology Molecular function • thrombin activity • receptor binding • calcium ion binding Cellular component • extracellular region • extracellular space • soluble fraction Biological process • regulation of progression through cell cycle • proteolysis • apoptosis • caspase activation • acute-phase response • tyrosine phosphorylation of STAT protein • STAT protein nuclear translocation • multicellular organismal development • blood coagulation • response to wounding • platelet activation • regulation of blood coagulation • fibrinolysis Sources: Amigo / EGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	2147	14061
Ensembl	ENSG00000180210	ENSMUSG00000027249
UniProt	P00734	Q3TJ94
RefSeq (mRNA)	NM_000506	NM_010168
RefSeq (protein)	NP_000497	NP_034298
Location (UCSC)	Chr 11: 46.7 - 46.72 Mb	Chr 2: 91.43 - 91.44 Mb
PubMed search	[1]	[2]

Thrombin (activated Factor II [IIa]) is a coagulation protein in the blood stream that has many effects in the coagulation cascade. It is a serine protease (EC 3.4.21.5) that converts soluble fibrinogen into insoluble strands of fibrin, as well as catalyzing many other coagulation-related reactions.

Genetics

The Thrombin (prothrombin) gene is located on the eleventh chromosome (11p11-q12). The molecular weight of prothrombin is approximately 72000 gmol^-1. The catalytic domain is released from prothrombin fragment 1.2 to create the active enzyme thrombin, which has a molecular weight of 36000 gmol^-1.

There are an estimated 30 people in the world that have been diagnosed with the congenital form of Factor II deficiency,^[2] which should not be confused with a mutation of prothrombin. The prothrombin gene mutation is called Factor II mutation. Factor II mutation is congenital.^[3] The Factor II mutated gene is not usually accompanied by other factor mutations (i.e. the most common is Factor V Leiden). The gene may be inherited heterozygous (1 pair), or much more rarely, homozygous (2 pairs), and is not related to gender or blood type. Homozygous mutations increase the risk of thrombosis more than heterozygous mutations, but the relative increased risk is not well documented. Other potential risks for thrombosis, such as oral contraceptives may be additive. The previously reported relationship of inflammatory bowel disease (i.e. Crohn's disease or Ulcerative Colitis) and prothrombin mutation or Factor V Leiden mutation have been contradicted by research.^[4]

Anchoring of bovine prothrombin to the membrane through its Gla domain

Physiology

Generation

Thrombin is produced by the enzymatic cleavage of two sites on prothrombin by activated Factor X (Xa). The activity of factor Xa is greatly enhanced by binding to activated Factor V (Va), termed the prothrombinase complex. Prothrombin is produced in the liver and is post-translationally modified in a vitamin K-dependent reaction that converts ten glutamic acids on prothrombin to gamma-carboxyglutamic acid (Gla). In the presence of calcium, the Gla residues promote the binding of prothrombin to phospholipid bilayers (see the picture). Deficiency of vitamin K or administration of the anticoagulant warfarin inhibits the production of gamma-carboxyglutamic acid residues, slowing the activation of the coagulation cascade.

In human adults the normal blood level of antithrombin activity has been measured to be around 1.1 units /ml. Newborn levels of thrombin steadily increase after birth to reach normal adult levels, from a level of around 0.5 units/ml 1 day after birth, to a level of around 0.9 units/ml after 6 months of life.^[5]

Action

Thrombin converts fibrinogen to an active form that assembles into fibrin. Thrombin also activates factor XI,^[6] factor V, and factor VIII. This positive feedback accelerates the production of thrombin.

Factor XIII is also activated by thrombin. Factor XIIIa is a transglutaminase that catalyzes the formation of covalent bonds between lysine and glutamine residues in fibrin. The covalent bonds increase the stability of the fibrin clot.

Platelets

In addition to its activity in the coagulation cascades, thrombin also promotes platelet activation, via activation of protease-activated receptors on the platelet.

Negative feedback

Thrombin bound to thrombomodulin activates protein C, an inhibitor of the coagulation cascade. The activation of protein C is greatly enhanced following the binding of thrombin to thrombomodulin, an integral membrane protein expressed by endothelial cells. Activated protein C inactivates factors Va and VIIIa. Binding of activated protein C to protein S leads to a modest increase in its activity.

Role in disease

Activation of prothrombin is crucial in physiological and pathological coagulation. Various rare diseases involving prothrombin have been described (e.g., hypoprothrombinemia). Anti-thrombin antibodies in autoimmune disease may be a factor in the formation of the lupus anticoagulant also known as (antiphospholipid syndrome). Hyperprothrombinemia can be caused by a mutation at 20210a.

Thrombin, a potent vasoconstrictor and mitogen, is implicated as a major factor in vasospasm following subarachnoid hemorrhage. Blood from a ruptured cerebral aneurysm clots around a cerebral artery, releasing thrombin. This can induce an acute and prolonged narrowing of the blood vessel, potentially resulting in cerebral ischemia and infarction (stroke).

Biotechnology

Due to its high proteolytic specificity, thrombin is a valuable biochemical tool. The thrombin cleavage site (Leu-Val-Pro-Arg-Gly-Ser) is commonly included in linker regions of recombinant fusion protein constructs. Following purification of the fusion protein, thrombin can be used to selectively cleave between the Arginine and Glycine residues of the cleavage site, effectively removing the purification tag from the protein of interest with a high degree of specificity.

Pharmacology

Prothrombin complex concentrate and fresh frozen plasma are prothrombin-rich coagulation factor preparations that can be used to correct deficiencies (usually due to medication) of prothrombin. Indications include intractable bleeding due to warfarin.

Manipulation of prothrombin is central to the mode of action of most anticoagulants. Warfarin and related drugs inhibit vitamin K-dependent carboxylation of several coagulation factors, including prothrombin. Heparin increases the affinity of antithrombin to thrombin (as well as factor Xa). The direct thrombin inhibitors, a newer class of medication, directly inhibit thrombin by binding to its active site.

Use in food production

Thrombin is sold under the brand name Fibrimex for use as a binding agent for meat. The thrombin in Fibrimex derives from pigs or bovine blood.^[7] According to the manufacturer it can be used to produce new kinds of mixed meats (for example combining beef and fish seamlessly). The manufacturer also states that it can be used to combine scrap meat into whole steaks which can then be sold to a higher price, thus cutting down on production costs.^[8]

Criticism against use in food production

General secretary Jan Bertoft of Sveriges Konsumenter (The Consumer Coalition of Sweden) has stated that "there is danger of misleading the consumers since there is no way to tell this reconstituted meat from real meat"^[7]

History

After the description of fibrinogen and fibrin, Alexander Schmidt hypothesised the existence of an enzyme that converts fibrinogen into fibrin in 1872.^[9]

Interactions

Thrombin has been shown to interact with Thrombomodulin.^[10][11]

See also

• The Proteolysis Map
• Fibrin glue

External links

• The MEROPS online database for peptidases and their inhibitors: S01.217
• GeneReviews/NCBI/NIH/UW entry on Prothrombin Thrombophilia
• [3] Anti-coagulation & proteases by The Proteolysis Map-animation
• [4] PMAP: The Proteolysis Map/Thrombin

References

Further reading

PDB Gallery 1a2c: STRUCTURE OF THROMBIN INHIBITED BY AERUGINOSIN298-A FROM A BLUE-GREEN ALGA   1a3b: COMPLEX OF HUMAN ALPHA-THROMBIN WITH THE BIFUNCTIONAL BORONATE INHIBITOR BOROLOG1   1a3e: COMPLEX OF HUMAN ALPHA-THROMBIN WITH THE BIFUNCTIONAL BORONATE INHIBITOR BOROLOG2   1a46: THROMBIN COMPLEXED WITH HIRUGEN AND A BETA-STRAND MIMETIC INHIBITOR   1a4w: CRYSTAL STRUCTURES OF THROMBIN WITH THIAZOLE-CONTAINING INHIBITORS: PROBES OF THE S1' BINDING SITE   1a5g: HUMAN THROMBIN COMPLEXED WITH NOVEL SYNTHETIC PEPTIDE MIMETIC INHIBITOR AND HIRUGEN   1a61: THROMBIN COMPLEXED WITH A BETA-MIMETIC THIAZOLE-CONTAINING INHIBITOR   1abi: STRUCTURE OF THE HIRULOG 3-THROMBIN COMPLEX AND NATURE OF THE S' SUBSITES OF SUBSTRATES AND INHIBITORS   1abj: STRUCTURE OF THE HIRULOG 3-THROMBIN COMPLEX AND NATURE OF THE S' SUBSITES OF SUBSTRATES AND INHIBITORS   1ad8: COMPLEX OF THROMBIN WITH AND INHIBITOR CONTAINING A NOVEL P1 MOIETY   1ae8: HUMAN ALPHA-THROMBIN INHIBITION BY EOC-D-PHE-PRO-AZALYS-ONP   1aht: CRYSTAL STRUCTURE OF HUMAN ALPHA-THROMBIN COMPLEXED WITH HIRUGEN AND P-AMIDINOPHENYLPYRUVATE) AT 1.6 ANGSTROMS RESOLUTION   1ai8: HUMAN ALPHA-THROMBIN TERNARY COMPLEX WITH THE EXOSITE INHIBITOR HIRUGEN AND ACTIVE SITE INHIBITOR PHCH2OCO-D-DPA-PRO-BOROMPG   1aix: HUMAN ALPHA-THROMBIN TERNARY COMPLEX WITH EXOSITE INHIBITOR HIRUGEN AND ACTIVE SITE INHIBITOR PHCH2OCO-D-DPA-PRO-BOROVAL   1awf: NOVEL COVALENT THROMBIN INHIBITOR FROM PLANT EXTRACT   1awh: NOVEL COVALENT THROMBIN INHIBITOR FROM PLANT EXTRACT   1ay6: THROMBIN INHIBITOR FROM THEONALLA, CYCLOTHEANAMIDE-BASED MACROCYCLIC TRIPEPTIDE MOTIF   1b5g: HUMAN THROMBIN COMPLEXED WITH NOVEL SYNTHETIC PEPTIDE MIMETIC INHIBITOR AND HIRUGEN   1b7x: STRUCTURE OF HUMAN ALPHA-THROMBIN Y225I MUTANT BOUND TO D-PHE-PRO-ARG-CHLOROMETHYLKETONE   1ba8: THROMBIN INHIBITOR WITH A RIGID TRIPEPTIDYL ALDEHYDES   1bb0: THROMBIN INHIBITORS WITH RIGID TRIPEPTIDYL ALDEHYDES   1bbr: THE STRUCTURE OF RESIDUES 7-16 OF THE A ALPHA CHAIN OF HUMAN FIBRINOGEN BOUND TO BOVINE THROMBIN AT 2.3 ANGSTROMS RESOLUTION   1bcu: ALPHA-THROMBIN COMPLEXED WITH HIRUGEN AND PROFLAVIN   1bhx: X-RAY STRUCTURE OF THE COMPLEX OF HUMAN ALPHA THROMBIN WITH THE INHIBITOR SDZ 229-357   1bth: STRUCTURE OF THROMBIN COMPLEXED WITH BOVINE PANCREATIC TRYPSIN INHIBITOR   1c1u: RECRUITING ZINC TO MEDIATE POTENT, SPECIFIC INHIBITION OF SERINE PROTEASES   1c1v: RECRUITING ZINC TO MEDIATE POTENT, SPECIFIC INHIBITION OF SERINE PROTEASES   1c1w: RECRUITING ZINC TO MEDIATE POTENT, SPECIFIC INHIBITION OF SERINE PROTEASES   1c4u: SELECTIVE NON ELECTROPHILIC THROMBIN INHIBITORS WITH CYCLOHEXYL MOIETIES.   1c4v: SELECTIVE NON ELECTROPHILIC THROMBIN INHIBITORS WITH CYCLOHEXYL MOIETIES.   1c4y: SELECTIVE NON-ELECTROPHILIC THROMBIN INHIBITORS   1c5l: STRUCTURAL BASIS FOR SELECTIVITY OF A SMALL MOLECULE, S1-BINDING, SUB-MICROMOLAR INHIBITOR OF UROKINASE TYPE PLASMINOGEN ACTIVATOR   1c5n: STRUCTURAL BASIS FOR SELECTIVITY OF A SMALL MOLECULE, S1-BINDING, SUB-MICROMOLAR INHIBITOR OF UROKINASE TYPE PLASMINOGEN ACTIVATOR   1c5o: STRUCTURAL BASIS FOR SELECTIVITY OF A SMALL MOLECULE, S1-BINDING, SUB-MICROMOLAR INHIBITOR OF UROKINASE TYPE PLASMINOGEN ACTIVATOR   1ca8: THROMBIN INHIBITORS WITH RIGID TRIPEPTIDYL ALDEHYDES   1d3d: CRYSTAL STRUCTURE OF HUMAN ALPHA THROMBIN IN COMPLEX WITH BENZOTHIOPHENE INHIBITOR 4   1d3p: CRYSTAL STRUCTURE OF HUMAN APLHA-THROMBIN IN COMPLEX WITH BENZO[B]THIOPHENE INHIBITOR 3   1d3q: CRYSTAL STRUCTURE OF HUMAN ALPHA THROMBIN IN COMPLEX WITH BENZO[B]THIOPHENE INHIBITOR 2   1d3t: CRYSTAL STRUCTURE OF HUMAN ALPHA THROMBIN IN COMPLEX WITH BENZO[B]THIOPHENE INHIBITOR 1   1d4p: CRYSTAL STRUCTURE OF HUMAN ALPHA THROMBIN IN COMPLEX WITH 5-AMIDINOINDOLE-4-BENZYLPIPERIDINE INHIBITOR   1d6w: STRUCTURE OF THROMBIN COMPLEXED WITH SELECTIVE NON-ELECTROPHILIC INHIBITORS HAVING CYCLOHEXYL MOIETIES AT P1   1d9i: STRUCTURE OF THROMBIN COMPLEXED WITH SELECTIVE NON-ELECTOPHILIC INHIBITORS HAVING CYCLOHEXYL MOIETIES AT P1   1de7: INTERACTION OF FACTOR XIII ACTIVATION PEPTIDE WITH ALPHA-THROMBIN: CRYSTAL STRUCTURE OF THE ENZYME-SUBSTRATE COMPLEX   1dit: COMPLEX OF A DIVALENT INHIBITOR WITH THROMBIN   1dm4: SER195ALA MUTANT OF HUMAN THROMBIN COMPLEXED WITH FIBRINOPEPTIDE A (7-16)   1doj: Crystal structure of human alpha-thrombin*RWJ-51438 complex at 1.7 A   1dwb: CRYSTALLOGRAPHIC ANALYSIS AT 3.0-ANGSTROMS RESOLUTION OF THE BINDING TO HUMAN THROMBIN OF FOUR ACTIVE SITE-DIRECTED INHIBITORS   1dwc: CRYSTALLOGRAPHIC ANALYSIS AT 3.0-ANGSTROMS RESOLUTION OF THE BINDING TO HUMAN THROMBIN OF FOUR ACTIVE SITE-DIRECTED INHIBITORS   1dwd: CRYSTALLOGRAPHIC ANALYSIS AT 3.0-ANGSTROMS RESOLUTION OF THE BINDING TO HUMAN THROMBIN OF FOUR ACTIVE SITE-DIRECTED INHIBITORS   1dwe: CRYSTALLOGRAPHIC ANALYSIS AT 3.0-ANGSTROMS RESOLUTION OF THE BINDING TO HUMAN THROMBIN OF FOUR ACTIVE SITE-DIRECTED INHIBITORS   1dx5: CRYSTAL STRUCTURE OF THE THROMBIN-THROMBOMODULIN COMPLEX   1e0f: CRYSTAL STRUCTURE OF THE HUMAN ALPHA-THROMBIN-HAEMADIN COMPLEX: AN EXOSITE II-BINDING INHIBITOR   1eb1: COMPLEX STRUCTURE OF HUMAN THROMBIN WITH N-METHYL-ARGININE INHIBITOR   1eoj: DESIGN OF P1' AND P3' RESIDUES OF TRIVALENT THROMBIN INHIBITORS AND THEIR CRYSTAL STRUCTURES   1eol: DESIGN OF P1' AND P3' RESIDUES OF TRIVALENT THROMBIN INHIBITORS AND THEIR CRYSTAL STRUCTURES   1fpc: ACTIVE SITE MIMETIC INHIBITION OF THROMBIN   1fph: THE INTERACTION OF THROMBIN WITH FIBRINOGEN: A STRUCTURAL BASIS FOR ITS SPECIFICITY   1g30: THROMBIN INHIBITOR COMPLEX   1g32: THROMBIN INHIBITOR COMPLEX   1g37: CRYSTAL STRUCTURE OF HUMAN ALPHA-THROMBIN COMPLEXED WITH BCH-10556 AND EXOSITE-DIRECTED PEPTIDE   1ghv: A NOVEL SERINE PROTEASE INHIBITION MOTIF INVOLVING A MULTI-CENTERED SHORT HYDROGEN BONDING NETWORK AT THE ACTIVE SITE   1ghw: A NOVEL SERINE PROTEASE INHIBITION MOTIF INVOLVING A MULTI-CENTERED SHORT HYDROGEN BONDING NETWORK AT THE ACTIVE SITE   1ghx: A NOVEL SERINE PROTEASE INHIBITION MOTIF INVOLVING A MULTI-CENTERED SHORT HYDROGEN BONDING NETWORK AT THE ACTIVE SITE   1ghy: A NOVEL SERINE PROTEASE INHIBITION MOTIF INVOLVING A MULTI-CENTERED SHORT HYDROGEN BONDING NETWORK AT THE ACTIVE SITE   1gj4: SELECTIVITY AT S1, H2O DISPLACEMENT, UPA, TPA, SER190/ALA190 PROTEASE, STRUCTURE-BASED DRUG DESIGN   1gj5: SELECTIVITY AT S1, H2O DISPLACEMENT, UPA, TPA, SER190/ALA190 PROTEASE, STRUCTURE-BASED DRUG DESIGN   1h8d: X-RAY STRUCTURE OF THE HUMAN ALPHA-THROMBIN COMPLEX WITH A TRIPEPTIDE PHOSPHONATE INHIBITOR.   1h8i: X-RAY CRYSTAL STRUCTURE OF HUMAN ALPHA-THROMBIN WITH A TRIPEPTIDE PHOSPHONATE INHIBITOR.   1hag: THE ISOMORPHOUS STRUCTURES OF PRETHROMBIN2, HIRUGEN-AND PPACK-THROMBIN: CHANGES ACCOMPANYING ACTIVATION AND EXOSITE BINDING TO THROMBIN   1hah: THE ISOMORPHOUS STRUCTURES OF PRETHROMBIN2, HIRUGEN-AND PPACK-THROMBIN: CHANGES ACCOMPANYING ACTIVATION AND EXOSITE BINDING TO THROMBIN   1hai: THE ISOMORPHOUS STRUCTURES OF PRETHROMBIN2, HIRUGEN-AND PPACK-THROMBIN: CHANGES ACCOMPANYING ACTIVATION AND EXOSITE BINDING TO THROMBIN   1hao: COMPLEX OF HUMAN ALPHA-THROMBIN WITH A 15MER OLIGONUCLEOTIDE GGTTGGTGTGGTTGG (BASED ON NMR MODEL OF DNA   1hap: COMPLEX OF HUMAN ALPHA-THROMBIN WITH A 15MER OLIGONUCLEOTIDE GGTTGGTGTGGTTGG (BASED ON X-RAY MODEL OF DNA)   1hbt: HUMAN ALPHA-THROMBIN COMPLEXED WITH A PEPTIDYL PYRIDINIUM METHYL KETONE CONTAINING BIVALENT INHIBITOR   1hdt: STRUCTURE OF A RETRO-BINDING PEPTIDE INHIBITOR COMPLEXED WITH HUMAN ALPHA-THROMBIN   1hgt: STRUCTURE OF THE HIRUGEN AND HIRULOG 1 COMPLEXES OF ALPHA-THROMBIN   1hlt: THE STRUCTURE OF A NONADECAPEPTIDE OF THE FIFTH EGF DOMAIN OF THROMBOMODULIN COMPLEXED WITH THROMBIN   1hut: THE STRUCTURE OF ALPHA-THROMBIN INHIBITED BY A 15-MER SINGLE-STRANDED DNA APTAMER   1hxe: SERINE PROTEASE   1hxf: HUMAN THROMBIN COMPLEX WITH HIRUDIN VARIANT   1ihs: CRYSTAL STRUCTURE OF THE COMPLEX OF HUMAN ALPHA-THROMBIN AND NON-HYDROLYZABLE BIFUNCTIONAL INHIBITORS, HIRUTONIN-2 AND HIRUTONIN-6   1iht: CRYSTAL STRUCTURE OF THE COMPLEX OF HUMAN ALPHA-THROMBIN AND NON-HYDROLYZABLE BIFUNCTIONAL INHIBITORS, HIRUTONIN-2 AND HIRUTONIN-6   1jmo: Crystal Structure of the Heparin Cofactor II-S195A Thrombin Complex   1jou: Crystal Structure of Native S195A Thrombin with an Unoccupied Active Site   1jwt: CRYSTAL STRUCTURE OF THROMBIN IN COMPLEX WITH A NOVEL BICYCLIC LACTAM INHIBITOR   1k21: HUMAN THROMBIN-INHIBITOR COMPLEX   1k22: HUMAN THROMBIN-INHIBITOR COMPLEX   1kts: Thrombin Inhibitor Complex   1ktt: Thrombin inhibitor complex   1lhc: HUMAN ALPHA-THROMBIN COMPLEXED WITH AC-(D)PHE-PRO-BOROARG-OH   1lhd: HUMAN ALPHA-THROMBIN COMPLEXED WITH AC-(D)PHE-PRO-BOROLYS-OH   1lhe: HUMAN ALPHA-THROMBIN COMPLEXED WITH AC-(D)PHE-PRO-BORO-N-BUTYL-AMIDINO-GLYCINE-OH   1lhf: HUMAN ALPHA-THROMBIN COMPLEXED WITH AC-(D)PHE-PRO-BORO-HOMOLYS-OH   1lhg: HUMAN ALPHA-THROMBIN COMPLEXED WITH AC-(D)PHE-PRO-BOROORNITHINE-OH   1mh0: Crystal structure of the anticoagulant slow form of thrombin   1mu6: Crystal Structure of Thrombin in Complex with L-378,622   1mu8: thrombin-hirugen_l-378,650   1mue: Thrombin-Hirugen-L405,426   1nm6: thrombin in complex with selective macrocyclic inhibitor at 1.8A   1no9: Design of weakly basic thrombin inhibitors incorporating novel P1 binding functions: molecular and X-ray crystallographic studies.   The maximum number of images (100) is exceeded !