Prothrombin (coagulation factor II) is encoded in the human by the F2-gene. It is proteolytically cleaved during the clotting process by the prothrombinase enzyme complex to form thrombin.
Thrombin (Factor IIa) (EC3.4.21.5, fibrose, thrombase, thrombofort, topical, thrombin-C, tropostasin, activated blood-coagulation factor II, E thrombin, beta-thrombin, gamma-thrombin) is a serine protease, that converts fibrinogen into strands of insoluble fibrin, as well as catalyzing many other coagulation-related reactions.[5][6]
History
After the description of fibrinogen and fibrin, Alexander Schmidt hypothesised the existence of an enzyme that converts fibrinogen into fibrin in 1872.[7]
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 co-translationally modified in a vitamin K-dependent reaction that converts 10-12 glutamic acids in the N terminus of the molecule to gamma-carboxyglutamic acid (Gla).[11] In the presence of calcium, the Gla residues promote the binding of prothrombin to phospholipid bilayers. 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.[12]
Mechanism of action
In the blood coagulation pathway, thrombin acts to convert factor XI to XIa, VIII to VIIIa, V to Va, fibrinogen to fibrin, and XIII to XIIIa. In the conversion of fibrinogen into fibrin, thrombin catalyzes the cleavage of fibrinopeptides A and B from the respective Aα and Bβ chains of fibrinogen to form fibrin monomers.[13]
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. Thrombin interacts with thrombomodulin.[14][15]
As part of its activity in the coagulation cascade, thrombin also promotes platelet activation and aggregation via activation of protease-activated receptors on the cell membrane of 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. Thrombin is also inactivated by antithrombin, a serine protease inhibitor.
Structure
Anchoring of bovine prothrombin to the membrane through its Gla domain.[16]
The molecular weight of prothrombin is approximately 72,000 Da. The catalytic domain is released from prothrombin fragment 1.2 to create the active enzyme thrombin, which has a molecular weight of 36,000 Da. Structurally, it is a member of the large PA clan of proteases.
Prothrombin is composed of four domains; an N-terminal Gla domain, two kringle domains and a C-terminal trypsin-like serine protease domain.
Factor Xa with factor V as a cofactor leads to cleavage of the Gla and two Kringle domains (forming together a fragment called fragment 1.2) and leave thrombin, consisting solely of the serine protease domain.[17]
As is the case for all serine proteases, prothrombin is converted to active thrombin by proteolysis of an internal peptide bond, exposing a new N-terminal Ile-NH3. The historic model of activation of serine proteases involves insertion of this newly formed N-terminus of the heavy chain into the β-barrel promoting the correct conformation of the catalytic residues.[18] Contrary to crystal structures of active thrombin, hydrogen-deuterium exchange mass spectrometry studies indicate that this N-terminal Ile-NH3 does not become inserted into the β-barrel in the apo form of thrombin. However, binding of the active fragment of thrombomodulin appears to allosterically promote the active conformation of thrombin by inserting this N-terminal region.[19]
Gene
There are an estimated 30 people in the world that have been diagnosed with the congenital form of Factor II deficiency,[20] which should not be confused with the prothrombin G20210A mutation, which is also called the factor II mutation. Prothrombin G20210A is congenital.[21]
Prothrombin G20210A 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 G20210A or factor V Leiden mutation have been contradicted by research.[22]
Beyond its key role in the dynamic process of thrombus formation, thrombin has a pronounced pro-inflammatory character, which may influence the onset and progression of atherosclerosis. Acting via its specific cell membrane receptors (protease activated receptors: PAR-1, PAR-3 and PAR-4), which are abundantly expressed in all arterial vessel wall constituents, thrombin has the potential to exert pro-atherogenic actions such as inflammation, leukocyte recruitment into the atherosclerotic plaque, enhanced oxidative stress, migration and proliferation of vascular smooth muscle cells, apoptosis and angiogenesis.[23][24][25]
Thrombin is implicated in the physiology of blood clots. Its presence indicates the existence of a clot. In 2013 a system for detecting the presence of thrombin was developed in mice. It combines peptide-coated iron oxide attached to "reporter chemicals". When a peptide binds to a thrombin molecule, the report is released and appears in the urine where it can be detected. Human testing has not been conducted.[26]
Applications
Research tool
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.
Medicine and surgery
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.
Recombinant thrombin is available as a powder for reconstitution into aqueous solution. It can be applied topically during surgery, as an aid to hemostasis. It can be useful for controlling minor bleeding from capillaries and small venules, but ineffective and not indicated for massive or brisk arterial bleeding.[27][28][29]
Food production
Thrombin, combined with fibrinogen, is sold under the brand name Fibrimex for use as a binding agent for meat. Both proteins in Fibrimex derives from porcine or bovine blood.[30] 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 whole muscle meat, form and portion these, thus cutting down on production costs without a loss in quality.[31]
General secretary Jan Bertoft of Swedish Consumers' Association has stated that "there is danger of misleading the consumers since there is no way to tell this reconstituted meat from real meat".[30]
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^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Royle NJ, Irwin DM, Koschinsky ML, MacGillivray RT, Hamerton JL (May 1987). "Human genes encoding prothrombin and ceruloplasmin map to 11p11-q12 and 3q21-24, respectively". Somatic Cell and Molecular Genetics. 13 (3): 285–92. doi:10.1007/BF01535211. PMID3474786. S2CID45686258.
^Degen SJ, Davie EW (September 1987). "Nucleotide sequence of the gene for human prothrombin". Biochemistry. 26 (19): 6165–77. doi:10.1021/bi00393a033. PMID2825773.
^Schmidt A (1872). "Neue Untersuchungen ueber die Fasserstoffesgerinnung". Pflügers Archiv für die gesamte Physiologie. 6: 413–538. doi:10.1007/BF01612263. S2CID37273997.
^Kaushansky K, Lichtman M, Prchal J, Levi M, Press O, Burns L, Caligiuri M (2015). Williams Hematology. McGraw-Hill. p. 1918. ISBN9780071833011.
^Quick AJ (1957). Hemorrhagic Diseases. Philadelphia: Lea and Febiger. pp. 451–490. OCLC599096191.
^PDB: 1nl2; Huang M, Rigby AC, Morelli X, Grant MA, Huang G, Furie B, Seaton B, Furie BC (September 2003). "Structural basis of membrane binding by Gla domains of vitamin K-dependent proteins". Nature Structural Biology. 10 (9): 751–6. doi:10.1038/nsb971. PMID12923575. S2CID7751100.
^Davie EW, Kulman JD (April 2006). "An overview of the structure and function of thrombin". Seminars in Thrombosis and Hemostasis. 32 (Suppl 1): 3–15. doi:10.1055/s-2006-939550. PMID16673262. S2CID36616995.
^Huber R, Bode W (1978-03-01). "Structural basis of the activation and action of trypsin". Accounts of Chemical Research. 11 (3): 114–122. doi:10.1021/ar50123a006. ISSN0001-4842.
^Degen SJ, McDowell SA, Sparks LM, Scharrer I (February 1995). "Prothrombin Frankfurt: a dysfunctional prothrombin characterized by substitution of Glu-466 by Ala". Thrombosis and Haemostasis. 73 (2): 203–9. doi:10.1055/s-0038-1653751. PMID7792730. S2CID20144699.
^Bernstein CN, Sargent M, Vos HL, Rosendaal FR (February 2007). "Mutations in clotting factors and inflammatory bowel disease". The American Journal of Gastroenterology. 102 (2): 338–43. doi:10.1111/j.1572-0241.2006.00974.x. PMID17156138. S2CID19895315.
^Borissoff JI, Spronk HM, ten Cate H (May 2011). "The hemostatic system as a modulator of atherosclerosis". The New England Journal of Medicine. 364 (18): 1746–60. doi:10.1056/NEJMra1011670. PMID21542745.
^Chapman WC, Singla N, Genyk Y, McNeil JW, Renkens KL, Reynolds TC, Murphy A, Weaver FA (August 2007). "A phase 3, randomized, double-blind comparative study of the efficacy and safety of topical recombinant human thrombin and bovine thrombin in surgical hemostasis". Journal of the American College of Surgeons. 205 (2): 256–65. doi:10.1016/j.jamcollsurg.2007.03.020. PMID17660072.
^Singla NK, Ballard JL, Moneta G, Randleman CD, Renkens KL, Alexander WA (July 2009). "A phase 3b, open-label, single-group immunogenicity and safety study of topical recombinant thrombin in surgical hemostasis". Journal of the American College of Surgeons. 209 (1): 68–74. doi:10.1016/j.jamcollsurg.2009.03.016. PMID19651065.
^Greenhalgh DG, Gamelli RL, Collins J, Sood R, Mozingo DW, Gray TE, Alexander WA (2009). "Recombinant thrombin: safety and immunogenicity in burn wound excision and grafting". Journal of Burn Care & Research. 30 (3): 371–9. doi:10.1097/BCR.0b013e3181a28979. PMID19349898. S2CID3678462.
Lenting PJ, van Mourik JA, Mertens K (December 1998). "The life cycle of coagulation factor VIII in view of its structure and function". Blood. 92 (11): 3983–96. doi:10.1182/blood.V92.11.3983. PMID9834200.
Plow EF, Cierniewski CS, Xiao Z, Haas TA, Byzova TV (July 2001). "AlphaIIbbeta3 and its antagonism at the new millennium". Thrombosis and Haemostasis. 86 (1): 34–40. doi:10.1055/s-0037-1616198. PMID11487023. S2CID74389210.
Maragoudakis ME, Tsopanoglou NE, Andriopoulou P (April 2002). "Mechanism of thrombin-induced angiogenesis". Biochemical Society Transactions. 30 (2): 173–7. doi:10.1042/BST0300173. PMID12023846.
Howell DC, Laurent GJ, Chambers RC (April 2002). "Role of thrombin and its major cellular receptor, protease-activated receptor-1, in pulmonary fibrosis". Biochemical Society Transactions. 30 (2): 211–6. doi:10.1042/BST0300211. PMID12023853. S2CID32822567.
De Cristofaro R, De Candia E (June 2003). "Thrombin domains: structure, function and interaction with platelet receptors". Journal of Thrombosis and Thrombolysis. 15 (3): 151–63. doi:10.1023/B:THRO.0000011370.80989.7b. PMID14739624.
Tsopanoglou NE, Maragoudakis ME (February 2004). "Role of thrombin in angiogenesis and tumor progression". Seminars in Thrombosis and Hemostasis. 30 (1): 63–9. doi:10.1055/s-2004-822971. PMID15034798. S2CID260320933.
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 ALPHA-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.
1nrn: CRYSTALLOGRAPHIC STRUCTURES OF THROMBIN COMPLEXED WITH THROMBIN RECEPTOR PEPTIDES: EXISTENCE OF EXPECTED AND NOVEL BINDING MODES
1nro: CRYSTALLOGRAPHIC STRUCTURES OF THROMBIN COMPLEXED WITH THROMBIN RECEPTOR PEPTIDES: EXISTENCE OF EXPECTED AND NOVEL BINDING MODES
1nrp: CRYSTALLOGRAPHIC STRUCTURES OF THROMBIN COMPLEXED WITH THROMBIN RECEPTOR PEPTIDES: EXISTENCE OF EXPECTED AND NOVEL BINDING MODES
1nrq: CRYSTALLOGRAPHIC STRUCTURES OF THROMBIN COMPLEXED WITH THROMBIN RECEPTOR PEPTIDES: EXISTENCE OF EXPECTED AND NOVEL BINDING MODES
1nrr: CRYSTALLOGRAPHIC STRUCTURES OF THROMBIN COMPLEXED WITH THROMBIN RECEPTOR PEPTIDES: EXISTENCE OF EXPECTED AND NOVEL BINDING MODES
1nrs: CRYSTALLOGRAPHIC STRUCTURES OF THROMBIN COMPLEXED WITH THROMBIN RECEPTOR PEPTIDES: EXISTENCE OF EXPECTED AND NOVEL BINDING MODES
1nt1: thrombin in complex with selective macrocyclic inhibitor
1nu7: Staphylocoagulase-Thrombin Complex
1nu9: Staphylocoagulase-Prethrombin-2 complex
1ny2: Human alpha thrombin inhibited by RPPGF and hirugen
1nzq: D-Phe-Pro-Arg-Type Thrombin Inhibitor
1o0d: Human Thrombin complexed with a d-Phe-Pro-Arg-type Inhibitor and a C-terminal Hirudin derived exo-site inhibitor
1o2g: Elaborate Manifold of Short Hydrogen Bond Arrays Mediating Binding of Active Site-Directed Serine Protease Inhibitors
1o5g: Dissecting and Designing Inhibitor Selectivity Determinants at the S1 site Using an Artificial Ala190 Protease (Ala190 uPA)
1ook: Crystal Structure of the Complex of Platelet Receptor GPIb-alpha and Human alpha-Thrombin
1oyt: COMPLEX OF RECOMBINANT HUMAN THROMBIN WITH A DESIGNED FLUORINATED INHIBITOR
1p8v: CRYSTAL STRUCTURE OF THE COMPLEX OF PLATELET RECEPTOR GPIB-ALPHA AND ALPHA-THROMBIN AT 2.6A
1ppb: THE REFINED 1.9 ANGSTROMS CRYSTAL STRUCTURE OF HUMAN ALPHA-THROMBIN: INTERACTION WITH D-PHE-PRO-ARG CHLOROMETHYLKETONE AND SIGNIFICANCE OF THE TYR-PRO-PRO-TRP INSERTION SEGMENT
1qbv: CRYSTAL STRUCTURE OF THROMBIN COMPLEXED WITH AN GUANIDINE-MIMETIC INHIBITOR
1qhr: NOVEL COVALENT ACTIVE SITE THROMBIN INHIBITORS
1qj1: NOVEL COVALENT ACTIVE SITE THROMBIN INHIBITORS
1qj6: NOVEL COVALENT ACTIVE SITE THROMBIN INHIBITORS
1qj7: NOVEL COVALENT ACTIVE SITE THROMBIN INHIBITORS
1qur: HUMAN ALPHA-THROMBIN IN COMPLEX WITH BIVALENT, BENZAMIDINE-BASED SYNTHETIC INHIBITOR
1rd3: 2.5A Structure of Anticoagulant Thrombin Variant E217K
1riw: Thrombin in complex with natural product inhibitor Oscillarin
1t4u: Crystal Structure Analysis of a novel Oxyguanidine bound to Thrombin
1t4v: Crystal Structure Analysis of a novel Oxyguanidine bound to Thrombin
1ta2: Crystal structure of thrombin in complex with compound 1
1ta6: Crystal structure of thrombin in complex with compound 14b
1tb6: 2.5A Crystal Structure of the Antithrombin-Thrombin-Heparin Ternary Complex
1tbz: HUMAN THROMBIN WITH ACTIVE SITE N-METHYL-D PHENYLALANYL-N-[5-(AMINOIMINOMETHYL)AMINO]-1-[(BENZOTHIAZOLYL)CARBONYL] BUTYL]-L-PROLINAMIDE TRIFLUROACETATE AND EXOSITE-HIRUGEN
1thp: STRUCTURE OF HUMAN ALPHA-THROMBIN Y225P MUTANT BOUND TO D-PHE-PRO-ARG-CHLOROMETHYLKETONE
1thr: STRUCTURES OF THROMBIN COMPLEXES WITH A DESIGNED AND A NATURAL EXOSITE INHIBITOR
1ths: STRUCTURES OF THROMBIN COMPLEXES WITH A DESIGNED AND A NATURAL EXOSITE INHIBITOR
1tmb: MOLECULAR BASIS FOR THE INHIBITION OF HUMAN ALPHA-THROMBIN BY THE MACROCYCLIC PEPTIDE CYCLOTHEONAMIDE A
1tmt: CHANGES IN INTERACTIONS IN COMPLEXES OF HIRUDIN DERIVATIVES AND HUMAN ALPHA-THROMBIN DUE TO DIFFERENT CRYSTAL FORMS
1tmu: CHANGES IN INTERACTIONS IN COMPLEXES OF HIRUDIN DERIVATIVES AND HUMAN ALPHA-THROMBIN DUE TO DIFFERENT CRYSTAL FORMS
1tom: ALPHA-THROMBIN COMPLEXED WITH HIRUGEN
1tq0: Crystal structure of the potent anticoagulant thrombin mutant W215A/E217A in free form
1tq7: Crystal structure of the anticoagulant thrombin mutant W215A/E217A bound to PPACK
1twx: Crystal structure of the thrombin mutant D221A/D222K
1ucy: THROMBIN COMPLEXED WITH FIBRINOPEPTIDE A ALPHA (RESIDUES 7-19). THREE COMPLEXES, ONE WITH EPSILON-THROMBIN AND TWO WITH ALPHA-THROMBIN
1uma: ALPHA-THROMBIN (HIRUGEN) COMPLEXED WITH NA-(N,N-DIMETHYLCARBAMOYL)-ALPHA-AZALYSINE
1uvs: BOVINE THROMBIN--BM51.1011 COMPLEX
1vit: THROMBIN:HIRUDIN 51-65 COMPLEX
1vr1: Specificity for Plasminogen Activator Inhibitor-1
1vzq: COMPLEX OF THROMBIN WITH DESIGNED INHIBITOR 7165
1w7g: ALPHA-THROMBIN COMPLEX WITH SULFATED HIRUDIN (RESIDUES 54-65) AND L-ARGININE TEMPLATE INHIBITOR CS107
1way: ACTIVE SITE THROMBIN INHIBITORS
1wbg: ACTIVE SITE THROMBIN INHIBITORS
1xm1: Nonbasic Thrombin Inhibitor Complex
1xmn: Crystal structure of thrombin bound to heparin
1ycp: THE CRYSTAL STRUCTURE OF FIBRINOGEN-AA PEPTIDE 1-23 (F8Y) BOUND TO BOVINE THROMBIN EXPLAINS WHY THE MUTATION OF PHE-8 TO TYROSINE STRONGLY INHIBITS NORMAL CLEAVAGE AT ARGININE-16
1ype: Thrombin Inhibitor Complex
1ypg: Thrombin Inhibitor Complex
1ypj: Thrombin Inhibitor Complex
1ypk: Thrombin Inhibitor Complex
1ypl: X-ray crystal structure of thrombin inhibited by synthetic cyanopeptide analogue RA-1008
1ypm: X-ray crystal structure of thrombin inhibited by synthetic cyanopeptide analogue RA-1014
1z71: thrombin and P2 pyridine N-oxide inhibitor complex structure
1z8i: Crystal structure of the thrombin mutant G193A bound to PPACK
1z8j: Crystal structure of the thrombin mutant G193P bound to PPACK
1zgi: thrombin in complex with an oxazolopyridine inhibitor 21
1zgv: Thrombin in complex with an oxazolopyridine inhibitor 2
1zrb: Thrombin in complex with an azafluorenyl inhibitor 23b
2a0q: Structure of thrombin in 400 mM potassium chloride
2a2x: Orally Active Thrombin Inhibitors in Complex with Thrombin Inh12
2a45: Crystal structure of the complex between thrombin and the central ""E"" region of fibrin
2afq: 1.9 angstrom crytal structure of wild-type human thrombin in the sodium free state
2ank: orally active thrombin inhibitors in complex with thrombin and an exosite decapeptide
2anm: Ternary complex of an orally active thrombin inhibitor with human thrombin and a c-terminal hirudin derived exo-sit inhibitor
2b5t: 2.1 Angstrom structure of a nonproductive complex between antithrombin, synthetic heparin mimetic SR123781 and two S195A thrombin molecules
2bdy: thrombin in complex with inhibitor
2bvr: HUMAN THROMBIN COMPLEXED WITH FRAGMENT-BASED SMALL MOLECULES OCCUPYING THE S1 POCKET
2bvs: HUMAN THROMBIN COMPLEXED WITH FRAGMENT-BASED SMALL MOLECULES OCCUPYING THE S1 POCKET
2bvx: DESIGN AND DISCOVERY OF NOVEL, POTENT THROMBIN INHIBITORS WITH A SOLUBILIZING CATIONIC P1-P2-LINKER
2bxt: DESIGN AND DISCOVERY OF NOVEL, POTENT THROMBIN INHIBITORS WITH A SOLUBILIZING CATIONIC P1-P2-LINKER
2bxu: DESIGN AND DISCOVERY OF NOVEL, POTENT THROMBIN INHIBITORS WITH A SOLUBILIZING CATIONIC P1-P2-LINKER
2c8w: THROMBIN INHIBITORS
2c8x: THROMBIN INHIBITORS
2c8y: THROMBIN INHIBITORS
2c8z: THROMBIN INHIBITORS
2c90: THROMBIN INHIBITORS
2c93: THROMBIN INHIBITORS
2cf8: COMPLEX OF RECOMBINANT HUMAN THROMBIN WITH A INHIBITOR
2cf9: COMPLEX OF RECOMBINANT HUMAN THROMBIN WITH A INHIBITOR
2cn0: COMPLEX OF RECOMBINANT HUMAN THROMBIN WITH A DESIGNED INHIBITOR
2feq: orally active thrombin inhibitors
2fes: Orally active thrombin inhibitors
2gde: Thrombin in complex with inhibitor
2gp9: Crystal structure of the slow form of thrombin in a self-inhibited conformation
2h9t: Crystal structure of human alpha-thrombin in complex with suramin
2hgt: STRUCTURE OF THE HIRUGEN AND HIRULOG 1 COMPLEXES OF ALPHA-THROMBIN
2hnt: CRYSTALLOGRAPHIC STRUCTURE OF HUMAN GAMMA-THROMBIN
2hpp: STRUCTURES OF THE NONCOVALENT COMPLEXES OF HUMAN AND BOVINE PROTHROMBIN FRAGMENT 2 WITH HUMAN PPACK-THROMBIN
2hpq: STRUCTURES OF THE NONCOVALENT COMPLEXES OF HUMAN AND BOVINE PROTHROMBIN FRAGMENT 2 WITH HUMAN PPACK-THROMBIN
2hwl: Crystal structure of thrombin in complex with fibrinogen gamma' peptide
2jh0: HUMAN THROMBIN HIRUGEN INHIBITOR COMPLEX.
2jh5: HUMAN THROMBIN HIRUGEN INHIBITOR COMPLEX.
2jh6: HUMAN THROMBIN HIRUGEN INHIBITOR COMPLEX.
2od3: Human thrombin chimera with human residues 184a, 186, 186a, 186b, 186c and 222 replaced by murine thrombin equivalents.
2thf: STRUCTURE OF HUMAN ALPHA-THROMBIN Y225F MUTANT BOUND TO D-PHE-PRO-ARG-CHLOROMETHYLKETONE
3hat: ACTIVE SITE MIMETIC INHIBITION OF THROMBIN
4htc: THE REFINED STRUCTURE OF THE HIRUDIN-THROMBIN COMPLEX
4thn: THE CRYSTAL STRUCTURE OF ALPHA-THROMBIN-HIRUNORM IV COMPLEX REVEALS A NOVEL SPECIFICITY SITE RECOGNITION MODE.
5gds: HIRUNORMS ARE TRUE HIRUDIN MIMETICS. THE CRYSTAL STRUCTURE OF HUMAN ALPHA-THROMBIN:HIRUNORM V COMPLEX
7kme: CRYSTAL STRUCTURE OF HUMAN ALPHA-THROMBIN INHIBITED WITH SEL2711.
8kme: CRYSTAL STRUCTURE OF HUMAN ALPHA-THROMBIN INHIBITED WITH SEL2770.
![1d3p: CRYSTAL STRUCTURE OF HUMAN ALPHA-THROMBIN IN COMPLEX WITH BENZO[B]THIOPHENE INHIBITOR 3](File:PDB_1d3p_EBI.jpg)
![1d3q: CRYSTAL STRUCTURE OF HUMAN ALPHA THROMBIN IN COMPLEX WITH BENZO[B]THIOPHENE INHIBITOR 2](File:PDB_1d3q_EBI.jpg)
![1d3t: CRYSTAL STRUCTURE OF HUMAN ALPHA THROMBIN IN COMPLEX WITH BENZO[B]THIOPHENE INHIBITOR 1](File:PDB_1d3t_EBI.jpg)
![1tbz: HUMAN THROMBIN WITH ACTIVE SITE N-METHYL-D PHENYLALANYL-N-[5-(AMINOIMINOMETHYL)AMINO]-1-[(BENZOTHIAZOLYL)CARBONYL] BUTYL]-L-PROLINAMIDE TRIFLUROACETATE AND EXOSITE-HIRUGEN](File:PDB_1tbz_EBI.jpg)
