Fibrinopeptide structure

Superimposition of the three lead inhibitor and fibrinopeptide structures indicates the following design rules for thrombin inhibitors ... 

Fibrinogen is an elongated molecule with an (apy)2 structure.524,541,5413 Thrombin cleaves specific Arg-Gly bonds in the a and P chains releasing short (14- tol6-residue) "fibrinopeptides" from the N termini of the peptide chains. This leaves Gly-Pro-Arg "knobs" at... 

Peptide chimeras of this type have proven extremely valuable for the examination of an array of recognition events. In conjunction with molecular modeling, peptidomimetic substrates and inhibitors of human thrombin were designed and synthesized to evaluate our proposed structure for the thrombin-bound conformation of fibrinopeptide A (Scheme 2i)J%]... 

Figure 2.30. Domain structure of fibrinogen. The fibrinogen molecule is composed of globular end regions separated from a central domain by helical threads. The central domain has cross-links that hold all the polypeptide chains together. Fibrinopeptides A and B (FPA and FPB) are found in the central domain.

Figure 10.38. Structure of a Fibrinogen Molecule. (A) A ribbon diagram. The two rod regions are a-helical coiled coils, connected to a globular region at each end. (B) A schematic representation showing the positions of the fibrinopeptides A and B.

For thrombin, with fibrinogen as defining substrate, this is inconvenient. Inspection of complexes of thrombin with fibrinopeptide analogues jihhr, ldm4, Ijph, luGy, and lycp] shows the fibrinopeptide, the N-terminal fibrin cleavage product, to have a folded structure as illustrated in Fig. 7.1. (It is more convenient to use the notation of Fig. 7.2. [13]). 

Fig. 2. Structure of fibrinopeptide A and reaction products formed from thrombin attack on its natural and synthetic substrate.

Krishnan, R., Sadler, J.E., Tulinsky, A. 2000. Structure of the Serl95Ala mutant of human alpha-thrombin complexed with fibrinopeptide A(7-16) evidence for residual catalytic activity, Acta Crystallogr D 56, 406-410. 

Higher-resolution images reveal the detailed structure of the fibrin monomer, how the fibrin monomers come together, and how this assembly is facilitated by removal of the fibrinopeptides. The homologous (3 and y chains have globular domains at the carboxyl-terminal ends (Figure 10.40). These domains have binding holes that interact with peptides. The p domain is specific for sequences of the form HaN -Gly-His-Arg-, whereas the y domain binds HaN -Gly-Pro-Arg-. Exactly these sequences (some-... 

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