Peptides 3-pleated sheets

As a consequence of their different turn geometry a 10-membered turn closed by H-bonds between NH and C=0 +i and a 12-membered turn closed by Id-bonds between C=0 and NH +3, antiparallel hairpins formed by y9-peptides 121 and 122 display opposite sheet polarities (see Fig. 2.30A and B). Comparison of backbone torsion angles (X-ray and NMR) for selected y9-amino acids residues within extended strand segments of peptides 117-122 are shown in Tab. 2.7. The observed values are close to ideal values for y9-peptide pleated sheets =-120° (or 120°), 01 = 180°, (/ =120°(or-120°). 

The two peptides form a symmetrical dimer stabilized by four hydrogen bonds (red dashes) and hydrophobic contacts. The two monomers form a four-stranded, anti-parallel pleated sheet. 

Fig. 2.28 X-ray crystal structures of parallel sheet-forming and all-un//fce-/F -peptides 116 and 117 [10, 191]. Views along the parallel amide planes and crystal packing diagram show the parallel pleated sheet arrangement (view perpendicular to the amide planes).

Folding of a peptide probably occurs coincident with its biosynthesis (see Chapter 38). The physiologically active conformation reflects the amino acid sequence, steric hindrance, and noncovalent interactions (eg, hydrogen bonding, hydrophobic interactions) between residues. Common conformations include a-helices and P pleated sheets (see Chapter 5). 

The essential distinction between the approaches used to formulate and evaluate proteins, compared with conventional low molecular weight drugs, lies in the need to maintain several levels of protein structure and the unique chemical and physical properties that these higher-order structures convey. Proteins are condensation polymers of amino acids, joined by peptide bonds. The levels of protein architecture are typically described in terms of the four orders of structure [23,24] depicted in Fig. 2. The primary structure refers to the sequence of amino acids and the location of any disulfide bonds. Secondary structure is derived from the steric relations of amino acid residues that are close to one another. The alpha-helix and beta-pleated sheet are examples of periodic secondary structure. Tertiary... 

D. Seebach, S. Abele, K. Gademann, B. Jaun, Pleated Sheets and Turns of /3-Peptides with Proteinogenic Side Chains , Angew. Chem., Int. Ed. 1999, 38, 1595- 1597. 

Secondary structures are regions of the peptide chain with a defined conformation (see p. 68) that are stabilized by H-bonds. In insulin (2), the a-helical areas are predominant, making up 57% of the molecule 6% consists of p-pleated-sheet structures, and 10% of p-turns, while the remainder (27%) cannot be assigned to any of the secondary structures. 

The influence of chain length and side-chain modifications of ACTH-derived peptides on active avoidance behaviour in rats will be discussed. H-Met(02)-Glu-His--Phe-D-Lys-Phe-OH (Org 2766) emerged from these studies as an orally active peptide with an increased potency and selectivity of action. Physico-chemical data (from the literature) on the reference peptide ACTH--(4-10) did not point to a preferred conformation in solution, whereas in the crystalline state an antiparallel 3-pleated sheet structure was found. At the receptor site we suggested an a-helical conformation in which the Phe and Met residues are close together. Additional support for this suggestion came from the behavioural activity of [des-Tyr", Met ]enkephalin and of cyclo--(-Phe-Met-cAhx-), eAhx merely serving as a spacer. 

For activity of ACTH-derived peptides at the receptor for pole-jumping activity, the basic requirement seems to be the presence of a Phe and Met residue in close proximity. It is interesting to see that Phe and Met are close together in an a-helical structure in ACTH peptides (and as intra-chain neighbours in Met-enkephalin) and in the crystalline state in ACTH-(4-10) as a 3-pleated sheet and in ACTH-(4-7) in the form of a horseshoe this close proximity is in line with the results of a Free-Wilson type of analysis. 

Oxytocin (OT) is a nonapeptide in which six amino acids form a ring closed by a disulfide bridge, while the ring itself forms an antiparallel pleated sheet. The tail portion of the peptide, composed of Pro-Leu-Gly-NHj, is also rigidly held in a folded conformation. Oxytocin causes the powerful contraction of some smooth muscles and plays a vital role in milk ejection (not to be confused with milk secretion, which is regulated by prolactin). It also has uterotonic action, contracting the muscles of the uterus, and is therefore used clinically to induce childbirth. 

The large molecule consists of a single peptide chain 35% P-sheet and 20% helical structure are found in the folded stmcture. The active site is a 1.2 nm deep conical cavity in the central pleated sheet, with a ion located at its bottom. Three histidine residues hold the Zn +, which also binds an HjO molecule. The active-site cavity is divided into hydrophilic and hydrophobic halves. The inhibitors of the enzyme replace the water on the Zn + ion and also block the fifth coordination site where COj should bind. 

There are a number of MHC class I and class II polymorphic molecules, all with substantially the same basic structure. The MHC class I molecule is a dimer consisting of a glycoslylated transmembrane peptide of molecular weight 45 kDa covalently linked to a 12 kDa peptide it is found on the surface of most nucleated cells within the body. It is believed that the polypeptide backbones fold in such as way as to form a platform of -pleated sheet structures to support a peptide binding cleft in which the antigen fragments are held and presented to the T cells. 

FIGURE 4-7 The /8 conformation of polypeptide chains. These top and side views reveal the R groups extending out from the /3 sheet and emphasize the pleated shape described by the planes of the peptide bonds. (An alternative name for this structure is /3-pleated sheet.) Hydrogen-bond cross-links between adjacent chains are also shown, (a) Antiparallel /3 sheet, in which the amino-terminal to carboxyl-terminal orientation of adjacent chains (arrows) is inverse, (b) Parallel f) sheet. 

The 3-sheet is another form of secondary structure in which all of the peptide bond components are involved in hydrogen bonding (Figure 2.7A). The surfaces of 3-sheets appear "pleated," and these structures are, therefore, often called "P-pleated sheets." When illus trations are made of protein structure, 3-strands are often visualized as broad arrows (Figure 2.7B). 

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