spacer
spacer

PDBsum entry 1hbt
Go to PDB code: 
protein Protein-protein interface(s) links
Hydrolase/hydrolase inhibitor PDB id
1hbt

 

 

 

 

Loading ...

 
JSmol PyMol  
Contents
Protein chains
27 a.a. *
250 a.a. *
17 a.a. *
Waters ×185
* Residue conservation analysis
PDB id:
1hbt
Name: Hydrolase/hydrolase inhibitor
Title: Human alpha-thrombin complexed with a peptidyl pyridinium methyl ketone containing bivalent inhibitor
Structure: Alpha-thrombin (small subunit). Chain: l. Synonym: coagulation factor ii, activation peptide fragment 1, activation peptide fragment 2, thrombin light chain, thrombin heavy chain. Engineered: yes. Alpha-thrombin (large subunit). Chain: h. Synonym: coagulation factor ii, activation peptide fragment 1,
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: dkfzp470k2111, f2. Gene: f2. Synthetic: yes
Biol. unit: Trimer (from PQS)
Resolution:
2.00Å     R-factor:   0.181    
Authors: P.H.Rehse,M.Cygler
Key ref:
P.H.Rehse et al. (1995). Crystal structure of a peptidyl pyridinium methyl ketone inhibitor with thrombin. Biochemistry, 34, 11537-11544. PubMed id: 7547884 DOI: 10.1021/bi00036a029
Date:
06-Apr-95     Release date:   10-Jul-95    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		622 a.a.
27 a.a.
Protein chain
P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		622 a.a.
250 a.a.
Protein chain
No UniProt id for this chain
Struc: 17 a.a.
Key:    Secondary structure  CATH domain

 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.

 

 
DOI no: 10.1021/bi00036a029 Biochemistry 34:11537-11544 (1995)
PubMed id: 7547884  
 
 
Crystal structure of a peptidyl pyridinium methyl ketone inhibitor with thrombin.
P.H.Rehse, T.Steinmetzer, Y.Li, Y.Konishi, M.Cygler.
 
  ABSTRACT  
 
The crystal structure of a complex between a bivalent peptidyl pyridinium methyl ketone inhibitor and human alpha-thrombin has been solved and refined at 2.0 A to an R factor of 0.18. The inhibitor, (D)cyclohexylalanine-Pro-Arg-(CH2N+C5H4CH2CO)-(Gly)4-Asp- Tyr-Glu-Pro-Ile-Pro-Glu-Glu-Ala-cyclo-hexylalanine-(D)Glu (coded P596), which forms a reversible covalent complex with thrombin, is highly potent with a Ki = 4.6 +/- 1.0 x 10(-14) M, lower than that of recombinant hirudin. The N-terminal, active-site-directed portion of the inhibitor is linked to the fibrinogen recognition exosite binding portion by a tetraglycine segment. The strong electron-withdrawing effect provided by the permanent positive charge on the pyridinium nitrogen makes the arginyl carbonyl carbon more susceptible to nucleophilic attack. In the crystal, a covalent P596-thrombin complex is observed. The electron density surrounding the active site portion and the pyridinium of the inhibitor is very well defined, clearly showing the existence of a covalent bond between the Ser195 O gamma and the now tetrahedral carbon of the inhibitor. The decreased binding ability of thrombin inhibitors containing N-terminal acetylation is discussed as is the effect of replacing the P3 (D)phenylalanine with (D)cyclohexylalanine. The electron density surrounding the remainder of the inhibitor is generally well defined, the exceptions being the C-terminal (D)Glu, the highly flexible tetraglycine linker, and some of the solvent-directed side chains.(ABSTRACT TRUNCATED AT 250 WORDS)
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
10694407 J.J.Slon-Usakiewicz, J.Sivaraman, Y.Li, M.Cygler, and Y.Konishi (2000).
Design of P1' and P3' residues of trivalent thrombin inhibitors and their crystal structures.
  Biochemistry, 39, 2384-2391.
PDB codes: 1eoj 1eol
10987367 T.Steinmetzer, M.Batdordshjin, F.Pineda, L.Seyfarth, A.Vogel, S.Reissmann, J.Hauptmann, and J.Stürzebecher (2000).
New bivalent thrombin inhibitors with N(alpha)(methyl)arginine at the P1-position.
  Biol Chem, 381, 603-610.  
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.  
10504391 T.Steinmetzer, M.Renatus, S.Künzel, A.Eichinger, W.Bode, P.Wikström, J.Hauptmann, and J.Stürzebecher (1999).
Design and evaluation of novel bivalent thrombin inhibitors based on amidinophenylalanines.
  Eur J Biochem, 265, 598-605.
PDB code: 1qur
9772168 E.Skordalakes, S.Elgendy, C.A.Goodwin, D.Green, M.F.Scully, V.V.Kakkar, J.M.Freyssinet, G.Dodson, and J.J.Deadman (1998).
Bifunctional peptide boronate inhibitors of thrombin: crystallographic analysis of inhibition enhanced by linkage to an exosite 1 binding peptide.
  Biochemistry, 37, 14420-14427.
PDB codes: 1a3b 1a3e
9618463 K.Kamata, H.Kawamoto, T.Honma, T.Iwama, and S.H.Kim (1998).
Structural basis for chemical inhibition of human blood coagulation factor Xa.
  Proc Natl Acad Sci U S A, 95, 6630-6635.
PDB codes: 1xka 1xkb
  9792427 S.Tada, and J.J.Blow (1998).
The replication licensing system.
  Biol Chem, 379, 941-949.  
9109667 C.S.Cassidy, J.Lin, and P.A.Frey (1997).
A new concept for the mechanism of action of chymotrypsin: the role of the low-barrier hydrogen bond.
  Biochemistry, 36, 4576-4584.  
9313859 E.J.Enyedy, and I.M.Kovach (1997).
Modulation of human alpha-thrombin activity with phosphonate ester inhibitors.
  Bioorg Med Chem, 5, 1531-1541.  
9354617 J.J.Slon-Usakiewicz, E.Purisima, Y.Tsuda, T.Sulea, A.Pedyczak, J.Féthière, M.Cygler, and Y.Konishi (1997).
Nonpolar interactions of thrombin S' subsites with its bivalent inhibitor: methyl scan of the inhibitor linker.
  Biochemistry, 36, 13494-13502.  
9667850 W.C.Ripka (1997).
New thrombin inhibitors in cardiovascular disease.
  Curr Opin Chem Biol, 1, 242-253.  
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 codes are shown on the right.

 

spacer
spacer