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Thrombin
 Peptide & Chromogenic substrates
Natural inhibitors
Synthetic inhibitors
Other ligands
tPA
Natural Substrates
 Peptide & Chromogenic substrates
Natural inhibitors
Synthetic inhibitors
Other ligands
Factor Xa
Natural Substrates
 Peptide & Chromogenic substrates
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Catalog of thrombin natural substrates
Thrombin is involved in multiple roles: fibrinolysis, platelet aggregation, coagulation, anticoagulation, vascular endothellium, peripheral blood cell activation, cell growth, cellular migration. So this enzyme cleaves many different proteins. Most of these proteins interact with more than the active site. Some of them need the presence of cofactors to get a nominal activity.
The following table give the sequences of the substrates cut by thrombin between the P1 and P1' residues according to the nomenclature of Schechter and Berger.
Protein Substrates
Cut 9 8 7 6 5 4 3 2 1 1' 2' 3' 4' 5' 6' 7' 8' 9' Ref
Fibrinogen (a-alpha), human 16 F L A E G G G V R G P R V V E R H   98
Fibrinogen (a-alpha), human 19 E G G G V R G P R V V V E R H Q S A 99
Fibrinogen (B-beta), human 14 N E E G F F S A R G H R P L D K     98
Factor XIII, human 36 T V E L E G V P R G V N L Q Q       100
Factor XIII, bovine 37 V E L Q G L V P R G F N P Q Q       100
Factor VIII, human 372 N S P S F I Q I R S V A K K H P K T 101
Factor VIII, human 740 L S N N A I G P R S F S Q N S R H P 101
Factor VIII, human 1313 Q N F V T Q S K R A L K Q F R L P L 101
Factor VIII, human 1689 D E D E N Q S P R S F Q K K T R H Y 101
Factor V, human 709 R L A A A L G I R S F R N S S L N Q 102
Factor V, human 1018 T H H A P L S P R T F H P L R S E A 102
Factor V, human 1545 D N I A A W Y L R S N N G N R R N Y 102
Factor VII, human 152 R N A S K P Q G R I V G G K V C P K 103
Factor VII, bovine 1                 R G V T A           104
Prothrombin, human 155 Q V T V M V T P R S E G S S V N L   105
Prothrombin, human 286 R P L T F F N P R T F G S G E A N   107
Prothrombin, bovine 156 R V T V E V T P R S G G S T T S Q   108
Protein C, human 169 D Q G D Q V D P R L I D G K M T R R 110
Protein C, bovine 171 D Q K D Q L D P R I V D G Q E A G W 111
Secretin, bovine 14 F T S E L S R L R D S A R L Q R L   112
Chorionic b-chain, human 8   S K E P L R P R C R P I N A T L   113
Chorionic b-chain, human 60 L P Q V V C N Y R D V R F E S I R   113
Chorionic b-chain, human 74 S I R L P G C P R G V N P V V S Y   113
Chorionic b-chain, human 94 L S C Q C A L C R R S T T D C G G   113
Chymotrypsinogen, bovine 15 Q P V L S G L S R I V N G E E A V   114
Lysozyme, egg white 125 G T D V Q A W I R G C R L           115
Cholecystokinin, porcine 6       K A P S G R V S M I K N L Q   116
Growth hormone, human 133 G R L E D G S P R T G Q I F K Q T   117
Growth hormone, bovine 131 R E L E D G T P R A G Q I L K Q T   117
Growth hormone, ovine 52 R E L E D V T P R A G Q I L K Q T   117
Actin, rabbit skeletal muscle 28 G F A G D D A P R A V F P S I V G   118
Actin, rabbit skeletal muscle 39 F P S I V G R P R H Q G V M V G M   118
Actin, rabbit skeletal muscle 113 L T E A P L N P K A N R E K M T Q   118
Apolipoprotein-C-III-1 40 S Q Q V A A Q Q R G W V T D G F S   119
Troponin C 120 A G E L A E I F R A S G Q H V T D   120
Thrombin receptor, human 17 A T N A T L D P R S F L L R N P N D 121
                                         
                                         
                                         
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Peptides derived from thrombin natural substrates

The following table give the sequences of peptide issued from natural substrates cut by thrombin between the P1 and P1' residues according to the nomenclature of Schechter and Berger.
Peptides                            
Fibrinopeptide A                            
Fibrinopeptide B                            
                             
                             
                             
                             
                             
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Thrombin chromogenic substrates

The following table give the sequences of chromogenicl substrates cut by thrombin between the P1 and P1' residues according to the nomenclature of Schechter and Berger.
Peptides Chromogenic group = X     3 2 1 1'              
FPR para-nitro-anilide     d-F P R X              
FPK para-nitro-anilide     d-F P K X              
FGR para-nitro-anilide     d-F G R X              
VGK para-nitro-anilide     d-V G K X              
FPR para-nitro-anilide     d-F P R X              
VPK para-nitro-anilide     d-V P K X              
VGR para-nitro-anilide     d-V G R X              
VGK para-nitro-anilide     d-V G K X              

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Thrombin natural inhibitors
20% of plasma protein are protease inhibitors and most of these proteins are targetting serine proteases

alpha-2-macroglobuline (a2M): 2-4 identical sub-units of 180 kDa The inhibition is proceeded by caging proteases: no interaction with active sites. Sequence identity can be as low as 20% in this group.

Serpins: superfamily represented by alpha-1-antitrypsin (a1PI) 394 aa, highly glycosylated,

Kunins: superfamily represented by aprotinin or pancreatic trypsin inhibitor containing a kunin domain of 58 aa. Sequence identity of these domains embeded in many proteins, sometimes at several copies in the same chain, can be as low as 20%.

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Thierry Rose, PhD and Enrico Di Cera, MD
Department of Biochemistry and Molecular Biophysics
Washington University School of Medicine
Saint Louis, MO, U.S.A.
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