Turn regions

In most cases, pyrazino[l,2- ]pyrazines have been synthesized as highly saturated derivatives with the aim of preparing conformationally restricted compounds which mimic the secondary structure of reverse-turn regions of peptides and proteins. The saturated pyrazino[l,2- ]pyrazine 241 was synthesized from readily available starting materials, the key steps being the preparation of the keto amide 239 and subsequent tandem cyclizations from [6+0] atom fragments (Scheme 42) <20000L301>. 

The MMP enzyme family is part of the superfamily of metzincins. The metzincin superfamily is distinguished by a conserved zinc binding motif for the catalytic zinc and a Met-turn region [4]. The MMPs are unique in that they also contain a second structural zinc, however this zinc may be absent in the intact full-length enzyme [5]. The presence of one to four structural calcium ions has been detected in the MMPs that have been characterized to date. The importance of the zinc ions and at least one of the structural calcium ions to enzymatic activity has been proven [6]. 

Fig. 6.14 Representative snapshots of the insertion process of the model hairpin with a hydrophilic turn region. (Reprinted from Fig. 3 of ref. 76 with permission from the author).

Several crystal structure analyses of individual repressors and of repressor-operator complexes disclosed a recurrent template on the protein side. It consists of an a-helix/turn/a-helix motif with an almost invariant glycine in the turn region [707-710]. Most of the repressors so far investigated display such a motif but the interactions with the operator DNA, which occur in the major groove are individually different. Here we consider more closely the well-documented complexes between the N-terminal fragment of the repressor from phage 434 and its specific operator DNA [711], and the ternary complex formed between tryptophan repressor, tryptophan and DNA [712, 713]. 

Some methods provide three-state prediction (i.e., locating helices, sheets and coil regions) and others four-state prediction (the former plus p-turns). For the present analysis only three-state predictions were analyzed, and the four-state predictions were transformed to three-state ones by assigning the coil state to predicted turn regions. 

The conformations of turn regions depend primarily on the positions of certain amino acid residnes (usually Gly, Pro or Asn) in the loop (Hutchinson and Thornton, 1994). The type I P turn can accommodate any amino acid at positions i through i + 3, except that Pro cannot be at position i -i- 2. For the type I and II P turns, Gly and Pro predominate at positions i + 3 and i + 1 respectively, whereas Asn, Asp, Cys and Ser occur fie-quently at position i. The type II P turn shows preference for Gly and Asn at position i + 2. Gly occurs at positions i + 1 and i -i- 2 in type T as well as type IIT turns, and i + 1 in type IT turns. The conformation of the type HI turn corresponds to that of one turn of the 3.0io-helix, while Type Via and VIb have a cis peptide bond. 

Bartlett and co-workers at the University of California at Berkeley targeted the development of a peptide mimetic scaffold that would present the key molecular recognition features of the three amino acid binding loop to a-amylase. The cyclic peptides cyclo(D-Pro-Phe-Ala-Trp-Arg-Tyr) and cyclo(D-Pro-Phe-Ser-Trp-Arg-Tyr) were found to exhibit fC values of 14 and 32 pM, respectively, against a-amylase. The objective was then to locate a suitable mimic for the -turn region for incorporation into these cyclic peptides. 

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