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PDBsum entry 4baq

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protein ligands metals Protein-protein interface(s) links
Hydrolase PDB id
4baq
Jmol PyMol
Contents
Protein chains
28 a.a.
251 a.a.
Ligands
ASP-PHE-GLU-GLU-
ILE-PRO-GLU-GLU-
TYS-LEU
NAG
M4Z
Metals
_NA ×2
Waters ×196
PDB id:
4baq
Name: Hydrolase
Title: Thrombin in complex with inhibitor
Structure: Thrombin light chain. Chain: a. Synonym: coagulation factor ii. Thrombin heavy chain. Chain: b. Synonym: coagulation factor ii. Hirudin variant-1. Chain: d. Fragment: residues 53-64.
Source: Homo sapiens. Human. Organism_taxid: 9606. Synthetic: yes. Hirudo medicinalis. Organism_taxid: 6421
Resolution:
1.89Å     R-factor:   0.188     R-free:   0.220
Authors: Y.Xue,D.Musil
Key ref: J.Winquist et al. (2013). Identification of structural-kinetic and structural-thermodynamic relationships for thrombin inhibitors. Biochemistry, 52, 613-626. PubMed id: 23290007 DOI: 10.1021/bi301333z
Date:
14-Sep-12     Release date:   16-Jan-13    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin
Seq:
Struc:
 
Seq:
Struc:
622 a.a.
28 a.a.
Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin
Seq:
Struc:
 
Seq:
Struc:
622 a.a.
251 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains A, B: 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.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   1 term 
  Biological process     blood coagulation   2 terms 
  Biochemical function     calcium ion binding     2 terms  

 

 
DOI no: 10.1021/bi301333z Biochemistry 52:613-626 (2013)
PubMed id: 23290007  
 
 
Identification of structural-kinetic and structural-thermodynamic relationships for thrombin inhibitors.
J.Winquist, S.Geschwindner, Y.Xue, L.Gustavsson, D.Musil, J.Deinum, U.H.Danielson.
 
  ABSTRACT  
 
To improve our understanding of drug-target interactions, we explored the effect of introducing substituted amine residues with increased chain length in the P3 residue of the thrombin inhibitor melagatran. Inhibition, kinetic, and thermodynamic data obtained via stopped-flow spectroscopy (SF), isothermal microcalorimetry (ITC), and surface plasmon resonance (SPR) biosensor analysis were interpreted with the help of X-ray crystal structures of the enzyme-inhibitor complexes. The association rate became faster when the lipophilicity of the inhibitors was increased. This was coupled to an increased enthalpic component and a corresponding decreased entropic component. The dissociation rates were reduced with an increase in chain length, with only a smaller increase and a decrease in the enthalpic and entropic components, respectively. Overall, the affinity increased with an increase in chain length, with similar changes in the enthalpic and entropic components. ITC analysis confirmed the equilibrium data from SPR analysis, showing that the interaction of melagatran was the most enthalpy-driven interaction. Structural analysis of the thrombin-inhibitor complex showed that the orientation of the P1 and P2 parts of the molecules was very similar, but that there were significant differences in the interaction between the terminal part of the P3 side chain and the binding pocket. A combination of charge repulsion, H-bonds, and hydrophobic interactions could be used to explain the observed kinetic and thermodynamic profiles for the ligands. In conclusion, changes in the structure of a lead compound can have significant effects on its interaction with the target that translate directly into kinetic and thermodynamic effects. In contrast to what may be intuitively expected, hydrogen bond formation and breakage are not necessarily reflected in enthalpy gains and losses, respectively.
 

 

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