Thrombin structure

L. J. Berliner (1992) Thrombin, Structure Eunction, Plenum Press, New York. 

Olson ST, Bjork I. Regulation of thrombin by antithrombin and heparin cofactor II. In Berliner LJ, ed. Thrombin Structure and Function. New York Plenum Press, 1992 159-217. 

Bode W, Turk D, Karshikov A. The refined 1.9-A X-ray crystal structure of D-Phe-Pro-Arg chloromethylketone-inhibited human alpha-thrombin structure analysis, overall structure, electrostatic properties, detailed active-site geometry, and structure-function relationships. Protein Sci. 1992 1 426-471. 

About half of the thrombin structures in the PDB are active site complexes with covalent inhibitors and with other molecules bound to so-called exo-sites [17]. 

Figure 9-14. Schematic representation of the interaction of the N-terminal tripeptide of Y3NT with thrombin. The strnctnre of Y3NT was modeled on the structure of the hirudin-thrombin complex [4htc.pdb 31]. Relevant NT-thrombin distances, in the 2.5-3.5-A range, are indicated by dashed lines. Of note, w606, which in the wild-type hirudin-thrombin structure connects Tyr3 of the inhibitor to Tyr60a of the enzyme, is well suited as a hydrogen bond donor to stabilize the NT ring system [91].

Czodrowski, P., Sotriffer, C.A., and Klebe, G. (2007) Protonation changes upon ligand binding to trypsin and thrombin structural interpretation based on pfCa calculations and ITC experiments. Joumol of Molecular Biology, 367, 1347-1356. 

D, H W Hoeffken, D Crosse, J Stuerzebecher, P D Martin, B F P Edwards and W Bode 1992. Refined 2.3 Angstroms X-Ray Crystal Structure of Bovine Thrombin Complexes Formed witli he 3 Benzamidine and Arginine-Based Thrombin Inhibitors NAPAP, 4-TAPAP and MQPA A Starting Point for Improving Antithrombotics. Journal of Molecular Biology 226 1085-1099. 

D, J Sturzebecher and WBode 1991. Geometry of Binding of the N-Alpha-Tosylated Piperidides of weffl-Amidino-Phenylalanine, Para Amidino-Phenylalanine and para-Guanidino-Phenylalanine to Thrombin and Trypsin - X-ray Crystal Structures of Their Trypsin Complexes and Modeling of their Thrombin Complexes. FEBS Letters 287 133-138. 

Bode, W., et al. The refined 1.9 A crystal structure of human a-thrombin interaction with D-Phe-Pro-Arg chloromethylketone and significance of the Tyr-Pro-Pro-Trp insertion segment. EMBO ]. 8 3467-3475,... 

Grtitter, M.G., et al. Crystal structure of the thrombin-hirudin complex a novel mode of serine protease inhibition. EMBO J. 9 2361-2365, 1990. 

Fibrinolytics. Figure 2 Various fibrin structures for plasmin. Fibrinogen (Fg) is converted to fibrin (F) by thrombin (T), and thrombin can also convert factor XIII (XIII) to activated factor XIII (Xllla). The latter produces crosslinks between fibrins (FxxF) and also may crosslink fibrin with a2-plasmin inhibitor (FxxFxxPI). The efficiency of digestion of these plasmin substrates by plasmin, resulting in the soluble fibrin degradation products (FDP), is different. The amount of FDP formed in time is expressed in arbitrary units. 

Transition state theory, 46,208 Transmission factor, 42,44-46,45 Triosephosphate isomerase, 210 Trypsin, 170. See also Trypsin enzyme family active site of, 181 activity of, steric effects on, 210 potential surfaces for, 180 Ser 195-His 57 proton transfer in, 146, 147 specificity of, 171 transition state of, 226 Trypsin enzyme family, catalysis of amide hydrolysis, 170-171. See also Chymotrypsin Elastase Thrombin Trypsin Plasmin Tryptophan, structure of, 110... 

Fibrinolytic effecting protease enzyme from the poison secretion (venom) of Bothrops atrox with glycoprotein structure. It has thrombin similarly endopeptidase activity. 

Irreversible inhibition is probably due to the alkylation of a histidine residue.43 Chymotrypsin is selectively inactivated with no or poor inhibition of human leukocyte elastase (HLE) with a major difference the inactivation of HLE is transient.42,43 The calculated intrinsic reactivity of the coumarin derivatives, using a model of a nucleophilic reaction between the ligand and the methanol-water pair, indicates that the inhibitor potency cannot be explained solely by differences in the reactivity of the lactonic carbonyl group toward the nucleophilic attack 43 Studies on pyridyl esters of 6-(chloromethyl)-2-oxo-2//-1 -benzopyran-3-carboxylic acid (5 and 6, Fig. 11.5) and related structures having various substituents at the 6-position (7, Fig. 11.5) revealed that compounds 5 and 6 are powerful inhibitors of human leukocyte elastase and a-chymotrypsin thrombin is inhibited in some cases whereas trypsin is not inhibited.21... 

Wakselman, M. Mazaleyrat, J.-P. Lin, R. C. Xie, J. Vigier, B. Vilain, A. C. Fesquet, S. Boggetto, N. Reboud-Ravaux, M. Design, synthesis and study of a selective cyclopeptidic mechanism-based inhibitor of human thrombin. In Peptides Chemistry, Structure... 

Small-molecule direct thrombin inhibitors have been structurally modified for oral administration. Approximately... 

The concept that different structural domains on the heparin chains are principally involved for optimal activity in the foregoing interactions could not be perceived in early work on structure-activity correlations, because the activity of heparin has been most frequently evaluated only with whole-blood-clotting tests (such as the U.S.P. assay). Development of assays for specific clotting-factors (especially Factor Xa and thrombin) has permitted a better insight into the mechanism of action of heparin at different levels of the coagulation cascade. 

Stubbs M. T., Bode W. A player of many parts The spot light falls on thrombin s structure. Thromb Res 1993 69, 1-58. 

Rydel T. J., Ravichandran K. G., Tulinsky A., et al. The structure of a complex of recombinant hirudin and human alpha-thrombin. Science 1990 249,277-80. 

X-Ray crystal structures of four 6-strand-templated active site inhibitors of thrombin, including compounds MOL-126 and MOL-174 (Section 12.10.15.2 ), have been determined and refined at about 2.1 A resolution to crystallographic R-values between 0.148 and 0.164 <1999JME1376>. 

Kamm, W., Hauptmann, J., Behrens, I., Sturzebecher, J., Dullweber, F., Gohlke, H., Stubbs, M., Klebe, G., Kissel, T., Transport of peptido-mimetic thrombin inhibitors with a 3-amidino-phenylalanine structure permeability and efflux mechanism in monolayers of a human intestinal cell line (Caco-2), Pharm. Res. 2001, 18, 1110-1118. 

Figure 3. Chemical structures of the thrombin inhibitors for which calculations were carried out in Ref. 46 (BZA is benzamidine).

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