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PDBsum entry 1fph
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Hydrolase/hydrolase inhibitor PDB id
1fph

 

 

 

 

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Contents
Protein chains
36 a.a. *
259 a.a. *
12 a.a. *
12 a.a. *
Waters ×168
* Residue conservation analysis
PDB id:
1fph
Name: Hydrolase/hydrolase inhibitor
Title: The interaction of thrombin with fibrinogen: a structural basis for its specificity
Structure: Alpha-thrombin (small subunit). Chain: l. Alpha-thrombin (large subunit). Chain: h. Hirudin. Chain: i. Engineered: yes. Fibrinopeptide a. Chain: f.
Source: Homo sapiens. Human. Organism_taxid: 9606. Synthetic: yes. Synthetic: yes
Biol. unit: Tetramer (from PQS)
Resolution:
2.50Å     R-factor:   0.166    
Authors: M.T.Stubbs,W.Bode
Key ref: M.T.Stubbs et al. (1992). The interaction of thrombin with fibrinogen. A structural basis for its specificity. Eur J Biochem, 206, 187-195. PubMed id: 1587268
Date:
21-Apr-93     Release date:   31-Jan-94    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		622 a.a.
36 a.a.
Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		622 a.a.
259 a.a.
Protein chain
Pfam   ArchSchema ?
P28506  (HIR2B_HIRME) -  Hirudin-2B from Hirudo medicinalis
Seq:
Struc: 		65 a.a.
12 a.a.
Protein chain
Pfam   ArchSchema ?
P02671  (FIBA_HUMAN) -  Fibrinogen alpha chain from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		866 a.a.
11 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chains L, H: E.C.3.4.21.5  - thrombin.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Preferential cleavage: Arg-|-Gly; activates fibrinogen to fibrin and releases fibrinopeptide A and B.

 

 
Eur J Biochem 206:187-195 (1992)
PubMed id: 1587268  
 
 
The interaction of thrombin with fibrinogen. A structural basis for its specificity.
M.T.Stubbs, H.Oschkinat, I.Mayr, R.Huber, H.Angliker, S.R.Stone, W.Bode.
 
  ABSTRACT  
 
The structure of the ternary complex of human alpha-thrombin with a covalently bound analogue of fibrinopeptide A and a C-terminal hirudin peptide has been determined by X-ray diffraction methods at 0.25 nm resolution. Fibrinopeptide A folds in a compact manner, bringing together hydrophobic residues that slot into the apolar binding site of human alpha-thrombin. Fibrinogen residue Phe8 occupies the aryl-binding site of thrombin, adjacent to fibrinogen residues Leu9 and Val15 in the S2 subsite. The species diversity of fibrinopeptide A is analysed with respect to its conformation and its interaction with thrombin. The non-covalently attached peptide fragment hirudin(54-65) exhibits an identical conformation to that observed in the hirudin-thrombin complex. The occupancy of the secondary fibrinogen-recognition exosite by this peptide imposes restrictions on the manner of fibrinogen binding. The surface topology of the thrombin molecule indicates positions P1'-P3', differ from those of the canonical serine-proteinase inhibitors, suggesting a mechanical model for the switching of thrombin activity from fibrinogen cleavage to protein-C activation on thrombomodulin complex formation. The multiple interactions between thrombin and fibrinogen provide an explanation for the narrow specificity of thrombin. Structural grounds can be put forward for certain congenital clotting disorders.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19816721 H.L.de Amorim, P.A.Netz, and J.A.Guimarães (2010).
Thrombin allosteric modulation revisited: a molecular dynamics study.
  J Mol Model, 16, 725-735.  
20218626 M.A.Jadhav, G.Isetti, T.A.Trumbo, and M.C.Maurer (2010).
Effects of introducing fibrinogen Aalpha character into the factor XIII activation peptide segment.
  Biochemistry, 49, 2918-2924.  
19715676 L.Yang, S.H.Qureshi, C.Manithody, and A.R.Rezaie (2009).
Role of P2 glycine in determining the specificity of antithrombin reaction with coagulation proteases.
  Biochem Biophys Res Commun, 389, 162-167.  
18329094 E.Di Cera (2008).
Thrombin.
  Mol Aspects Med, 29, 203-254.  
18985012 M.Lepretti, S.Costantini, G.Ammirato, G.Giuberti, M.Caraglia, A.M.Facchiano, S.Metafora, and P.Stiuso (2008).
The N-terminal 1-16 peptide derived in vivo from protein seminal vesicle protein IV modulates alpha-thrombin activity: potential clinical implications.
  Exp Mol Med, 40, 541-549.  
17408413 C.A.Staton, S.M.Stribbling, C.García-Echeverría, J.P.Bury, S.Tazzyman, C.E.Lewis, and N.J.Brown (2007).
Identification of key residues involved in mediating the in vivo anti-tumor/anti-endothelial activity of Alphastatin.
  J Thromb Haemost, 5, 846-854.  
17347701 E.Di Cera, M.J.Page, A.Bah, L.A.Bush-Pelc, and L.C.Garvey (2007).
Thrombin allostery.
  Phys Chem Chem Phys, 9, 1291-1306.  
17635727 E.Di Cera (2007).
Thrombin as procoagulant and anticoagulant.
  J Thromb Haemost, 5, 196-202.  
16533041 I.Pechik, S.Yakovlev, M.W.Mosesson, G.L.Gilliland, and L.Medved (2006).
Structural basis for sequential cleavage of fibrinopeptides upon fibrin assembly.
  Biochemistry, 45, 3588-3597.
PDB code: 2a45
16230339 P.Panizzi, R.Friedrich, P.Fuentes-Prior, K.Richter, P.E.Bock, and W.Bode (2006).
Fibrinogen substrate recognition by staphylocoagulase.(pro)thrombin complexes.
  J Biol Chem, 281, 1179-1187.  
16207719 V.B.Louvain-Quintard, E.P.Bianchini, C.Calmel-Tareau, M.Tagzirt, and B.F.Le Bonniec (2005).
Thrombin-activable factor X re-establishes an intrinsic amplification in tenase-deficient plasmas.
  J Biol Chem, 280, 41352-41359.  
15892855 W.Bode (2005).
The structure of thrombin, a chameleon-like proteinase.
  J Thromb Haemost, 3, 2379-2388.  
16042075 Y.S.Sa, S.J.Kim, and H.S.Choi (2005).
The anticoagulant fraction from the leaves of Diospyros kaki L. has an antithrombotic activity.
  Arch Pharm Res, 28, 667-674.  
15152000 A.O.Pineda, C.J.Carrell, L.A.Bush, S.Prasad, S.Caccia, Z.W.Chen, F.S.Mathews, and E.Di Cera (2004).
Molecular dissection of Na+ binding to thrombin.
  J Biol Chem, 279, 31842-31853.
PDB codes: 1sfq 1sg8 1sgi 1shh
15286732 D.Gustafsson, R.Bylund, T.Antonsson, I.Nilsson, J.E.Nyström, U.Eriksson, U.Bredberg, and A.C.Teger-Nilsson (2004).
A new oral anticoagulant: the 50-year challenge.
  Nat Rev Drug Discov, 3, 649-659.  
15049836 G.Isetti, and M.C.Maurer (2004).
Probing thrombin's ability to accommodate a V34F substitution within the factor XIII activation peptide segment (28-41).
  J Pept Res, 63, 241-252.  
14978285 I.Pechik, J.Madrazo, M.W.Mosesson, I.Hernandez, G.L.Gilliland, and L.Medved (2004).
Crystal structure of the complex between thrombin and the central "E" region of fibrin.
  Proc Natl Acad Sci U S A, 101, 2718-2723.
PDB code: 1qvh
15075325 W.J.Carter, T.Myles, C.S.Gibbs, L.L.Leung, and J.A.Huntington (2004).
Crystal structure of anticoagulant thrombin variant E217K provides insights into thrombin allostery.
  J Biol Chem, 279, 26387-26394.
PDB code: 1rd3
11925440 E.P.Bianchini, V.B.Louvain, P.E.Marque, M.A.Juliano, L.Juliano, and B.F.Le Bonniec (2002).
Mapping of the catalytic groove preferences of factor Xa reveals an inadequate selectivity for its macromolecule substrates.
  J Biol Chem, 277, 20527-20534.  
12169660 T.P.Baglin, R.W.Carrell, F.C.Church, C.T.Esmon, and J.A.Huntington (2002).
Crystal structures of native and thrombin-complexed heparin cofactor II reveal a multistep allosteric mechanism.
  Proc Natl Acad Sci U S A, 99, 11079-11084.
PDB codes: 1jmj 1jmo
11901150 T.Rose, and E.Di Cera (2002).
Three-dimensional modeling of thrombin-fibrinogen interaction.
  J Biol Chem, 277, 18875-18880.  
11388453 H.S.Choi, and Y.S.Sa (2001).
Fibrinolytic and antithrombotic protease from Spirodela polyrhiza.
  Biosci Biotechnol Biochem, 65, 781-786.  
11593005 J.Madrazo, J.H.Brown, S.Litvinovich, R.Dominguez, S.Yakovlev, L.Medved, and C.Cohen (2001).
Crystal structure of the central region of bovine fibrinogen (E5 fragment) at 1.4-A resolution.
  Proc Natl Acad Sci U S A, 98, 11967-11972.
PDB codes: 1jy2 1jy3
10739913 R.Krishnan, J.E.Sadler, and A.Tulinsky (2000).
Structure of the Ser195Ala mutant of human alpha--thrombin complexed with fibrinopeptide A(7--16): evidence for residual catalytic activity.
  Acta Crystallogr D Biol Crystallogr, 56, 406-410.
PDB code: 1dm4
10380350 A.Lombardi, G.De Simone, S.Galdiero, N.Staiano, F.Nastri, and V.Pavone (1999).
From natural to synthetic multisite thrombin inhibitors.
  Biopolymers, 51, 19-39.  
10336381 M.C.Maurer, J.Y.Trosset, C.C.Lester, E.E.DiBella, and H.A.Scheraga (1999).
New general approach for determining the solution structure of a ligand bound weakly to a receptor: structure of a fibrinogen Aalpha-like peptide bound to thrombin (S195A) obtained using NOE distance constraints and an ECEPP/3 flexible docking program.
  Proteins, 34, 29-48.  
10380349 Y.Shimohigashi, T.Nose, Y.Yamauchi, and I.Maeda (1999).
Design of serine protease inhibitors with conformation restricted by amino acid side-chain-side-chain CH/pie interaction.
  Biopolymers, 51, 9.  
  9521099 G.De Simone, A.Lombardi, S.Galdiero, F.Nastri, R.Della Morte, N.Staiano, C.Pedone, M.Bolognesi, and V.Pavone (1998).
Hirunorms are true hirudin mimetics. The crystal structure of human alpha-thrombin-hirunorm V complex.
  Protein Sci, 7, 243-253.
PDB code: 5gds
9753458 M.M.Rooney, J.L.Mullin, and S.T.Lord (1998).
Substitution of tyrosine for phenylalanine in fibrinopeptide A results in preferential thrombin cleavage of fibrinopeptide B from fibrinogen.
  Biochemistry, 37, 13704-13709.  
9724521 R.Krishnan, E.Zhang, K.Hakansson, R.K.Arni, A.Tulinsky, M.S.Lim-Wilby, O.E.Levy, J.E.Semple, and T.K.Brunck (1998).
Highly selective mechanism-based thrombin inhibitors: structures of thrombin and trypsin inhibited with rigid peptidyl aldehydes.
  Biochemistry, 37, 12094-12103.
PDB codes: 1ba8 1bb0 1ca8 1yyy 1zzz
9200692 A.R.Rezaie (1997).
Role of Leu99 of thrombin in determining the P2 specificity of serpins.
  Biochemistry, 36, 7437-7446.  
9184147 A.Vindigni, C.E.White, E.A.Komives, and E.Di Cera (1997).
Energetics of thrombin-thrombomodulin interaction.
  Biochemistry, 36, 6674-6681.  
9306406 A.Vindigni, Q.D.Dang, and E.Di Cera (1997).
Site-specific dissection of substrate recognition by thrombin.
  Nat Biotechnol, 15, 891-895.  
9214615 A.van de Locht, W.Bode, R.Huber, B.F.Le Bonniec, S.R.Stone, C.T.Esmon, and M.T.Stubbs (1997).
The thrombin E192Q-BPTI complex reveals gross structural rearrangements: implications for the interaction with antithrombin and thrombomodulin.
  EMBO J, 16, 2977-2984.
PDB code: 1bth
  9232645 M.G.Malkowski, P.D.Martin, J.C.Guzik, and B.F.Edwards (1997).
The co-crystal structure of unliganded bovine alpha-thrombin and prethrombin-2: movement of the Tyr-Pro-Pro-Trp segment and active site residues upon ligand binding.
  Protein Sci, 6, 1438-1448.
PDB codes: 1mkw 1mkx
9342325 P.Fuentes-Prior, C.Noeske-Jungblut, P.Donner, W.D.Schleuning, R.Huber, and W.Bode (1997).
Structure of the thrombin complex with triabin, a lipocalin-like exosite-binding inhibitor derived from a triatomine bug.
  Proc Natl Acad Sci U S A, 94, 11845-11850.
PDB code: 1avg
9242618 Q.D.Dang, M.Sabetta, and E.Di Cera (1997).
Selective loss of fibrinogen clotting in a loop-less thrombin.
  J Biol Chem, 272, 19649-19651.  
9242661 R.Morenweiser, E.A.Auerswald, A.van de Locht, H.Fritz, J.Stürzebecher, and M.T.Stubbs (1997).
Structure-based design of a potent chimeric thrombin inhibitor.
  J Biol Chem, 272, 19938-19942.  
  9223519 R.Zhang, J.Durkin, W.T.Windsor, C.McNemar, L.Ramanathan, and H.V.Le (1997).
Probing the substrate specificity of hepatitis C virus NS3 serine protease by using synthetic peptides.
  J Virol, 71, 6208-6213.  
  9461350 V.Lauvrak, O.H.Brekke, O.Ihle, and B.H.Lindqvist (1997).
Identification and characterisation of C1q-binding phage displayed peptides.
  Biol Chem, 378, 1509-1519.  
8639675 A.R.Rezaie (1996).
Tryptophan 60-D in the B-insertion loop of thrombin modulates the thrombin-antithrombin reaction.
  Biochemistry, 35, 1918-1924.  
9022671 A.R.Rezaie, and C.T.Esmon (1996).
Molecular basis of residue 192 participation in determination of coagulation protease specificity.
  Eur J Biochem, 242, 477-484.  
8605191 A.Vindigni, and E.Di Cera (1996).
Release of fibrinopeptides by the slow and fast forms of thrombin.
  Biochemistry, 35, 4417-4426.  
8679538 B.F.Le Bonniec, T.Myles, T.Johnson, C.G.Knight, C.Tapparelli, and S.R.Stone (1996).
Characterization of the P2' and P3' specificities of thrombin using fluorescence-quenched substrates and mapping of the subsites by mutagenesis.
  Biochemistry, 35, 7114-7122.  
8662922 C.T.Esmon, and P.Lollar (1996).
Involvement of thrombin anion-binding exosites 1 and 2 in the activation of factor V and factor VIII.
  J Biol Chem, 271, 13882-13887.  
8987977 M.Tsiang, L.R.Paborsky, W.X.Li, A.K.Jain, C.T.Mao, K.E.Dunn, D.W.Lee, S.Y.Matsumura, M.D.Matteucci, S.E.Coutré, L.L.Leung, and C.S.Gibbs (1996).
Protein engineering thrombin for optimal specificity and potency of anticoagulant activity in vivo.
  Biochemistry, 35, 16449-16457.  
8784202 M.Z.Djie, B.F.Le Bonniec, P.C.Hopkins, K.Hipler, and S.R.Stone (1996).
Role of the P2 residue in determining the specificity of serpins.
  Biochemistry, 35, 11461-11469.  
8786410 P.D.Grootenhuis, and M.Karplus (1996).
Functionality map analysis of the active site cleft of human thrombin.
  J Comput Aided Mol Des, 10, 1.  
8855938 P.D.Martin, M.G.Malkowski, J.DiMaio, Y.Konishi, F.Ni, and B.F.Edwards (1996).
Bovine thrombin complexed with an uncleavable analog of residues 7-19 of fibrinogen A alpha: geometry of the catalytic triad and interactions of the P1', P2', and P3' substrate residues.
  Biochemistry, 35, 13030-13039.
PDB code: 1ucy
  8868478 R.Krishnan, A.Tulinsky, G.P.Vlasuk, D.Pearson, P.Vallar, P.Bergum, T.K.Brunck, and W.C.Ripka (1996).
Synthesis, structure, and structure-activity relationships of divalent thrombin inhibitors containing an alpha-keto-amide transition-state mimetic.
  Protein Sci, 5, 422-433.
PDB code: 1dit
7608183 A.R.Rezaie, and C.T.Esmon (1995).
Contribution of residue 192 in factor Xa to enzyme specificity and function.
  J Biol Chem, 270, 16176-16181.  
7673182 E.Di Cera, E.R.Guinto, A.Vindigni, Q.D.Dang, Y.M.Ayala, M.Wuyi, and A.Tulinsky (1995).
The Na+ binding site of thrombin.
  J Biol Chem, 270, 22089-22092.  
7479962 E.R.Guinto, A.Vindigni, Y.M.Ayala, Q.D.Dang, and E.Di Cera (1995).
Identification of residues linked to the slow-->fast transition of thrombin.
  Proc Natl Acad Sci U S A, 92, 11185-11189.  
7878739 M.T.Stubbs, and W.Bode (1995).
The clot thickens: clues provided by thrombin structure.
  Trends Biochem Sci, 20, 23-28.  
7622501 M.Tsiang, A.K.Jain, K.E.Dunn, M.E.Rojas, L.L.Leung, and C.S.Gibbs (1995).
Functional mapping of the surface residues of human thrombin.
  J Biol Chem, 270, 16854-16863.  
7559597 S.T.Lord, M.M.Rooney, K.P.Hopfner, and E.Di Cera (1995).
Binding of fibrinogen A alpha 1-50-beta-galactosidase fusion protein to thrombin stabilizes the slow form.
  J Biol Chem, 270, 24790-24793.  
8055928 A.R.Rezaie, and C.T.Esmon (1994).
Calcium inhibition of the activation of protein C by thrombin. Role of the P3 and P3' residues.
  Eur J Biochem, 223, 575-579.  
7518917 M.F.Kubik, A.W.Stephens, D.Schneider, R.A.Marlar, and D.Tasset (1994).
High-affinity RNA ligands to human alpha-thrombin.
  Nucleic Acids Res, 22, 2619-2626.  
8112314 M.Picozzi, R.Landolfi, and R.De Cristofaro (1994).
Effects of protons on the thrombin-fibrinogen interaction.
  Eur J Biochem, 219, 1013-1021.  
7712286 M.T.Stubbs, and W.Bode (1994).
Coagulation factors and their inhibitors.
  Curr Opin Struct Biol, 4, 823-832.  
  8251938 J.P.Priestle, J.Rahuel, H.Rink, M.Tones, and M.G.Grütter (1993).
Changes in interactions in complexes of hirudin derivatives and human alpha-thrombin due to different crystal forms.
  Protein Sci, 2, 1630-1642.
PDB codes: 1tmt 1tmu
8393788 M.C.Bouton, M.Jandrot-Perrus, A.Bezeaud, and M.C.Guillin (1993).
Late-fibrin(ogen) fragment E modulates human alpha-thrombin specificity.
  Eur J Biochem, 215, 143-149.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.

 

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