Oxytocin conformation

Fig. 26. A model of the hormone oxytocin, conformation with a concentration of the hydro-phobic groups on one side1...

T. L. Blundell, V.J. Hruby, A. Buku, A.J. Fischman, H.R. Wyssbrod, Crystal structure of deamino-oxytocin. Conformational flexibility and receptor binding. Science 232 633-636 (1986)... 

Hundreds of analogues of both oxytocin and vasopressin have been synthesized, and the conformations of many of these have been studied (22,23). 

The strategy of introducing non-natural aminoacids into the oxytocin peptide skeleton in order to make antagonists has also been exploited by Havaas et al. [51], who replaced the proline at the 7-position with sarcosine and modified the tyrosine residue at the 2-position to introduce further conformational constraint. A representative example is shown, (13), with a... 

J. B. A. Ross, W. R. Laws, A. Buku, J. C. Sutherland, and H. R. Wyssbrod, Time-resolved fluorescence and H NMR studies of tyrosyl residues in oxytocin and small peptides Correlation of NMR-determined conformations of tyrosyl residues and fluorescence decay kinetics, Biochemistry 25, 607-612 (1986). 

We have extensively Investigated the conformation-activity relationships of oxytocin (H-C s-Tyr-Ile-Gln-Asn-C s-Pro-Leu-Gly-NH2) antagonists based on the antagonist [Pen ]-oxytocln (. . 2) ... 

Our approach to testing this hypothesis and developing oxytocin antagonists with prolonged In vivo activity has been to further restrict the conformations of side chain groups at positions believed to be Important for binding In the antagonist... 

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. 

Vasopressin occurs in two variations arginine-vasopressin (AVP) and lysine-vasopressin (LVP), in which Arg is replaced by Lys. The conformation of these hormones is almost identical to that of oxytocin, except that the terminal tail is con-formationally free and not held by the ring. The physiological role of the vasopressins is the regulation of water reabsorption in the renal tubules (i.e., an antidiuretic action). In high doses, they promote the contraction of arterioles and capillaries and an increase in blood pressure hence the name of these hormones. Because of their very similar structures, OT and VP overlap in a number of effects. 

The C-terminal tripeptide tail of oxytocin H-L-Pro-Leu-Gly-NH2 (melanocyte-stimulating hormone release inhibiting factor, MIF or melanostatin) is implicated as having a direct effect on the central nervous system. The ALeu analogue of melanostatin, [ALeu2-MIF] was prepared in view of the earlier work on the active conformation of melanostatin in which a (3-turn was implicated.11771 ALeu was prepared by the N-chlorination/dehydrochlorination reaction and then coupled with Boc-Pro-OH. 

Examples of the way these two entirely different approaches compliment each other are developing in conformation studies with the hormones angiotensin, oxytocin, and vasopressin. In 1964 Craig, Harfenist, and Paladini (7) published the comparative half-escape times shown in Table I in 0.01N acetic acid and another series in Table II using a different membrane less porous and not as selective as the first. Oxytocin and vasopressin are cyclic octapeptides with an S-S linkage closing the ring at the 1-6 positions (5, 6). Their size is thus limited except for the side... 

It was postulated from the comparative data in Tables I and II and other observations that angiotensin had a definite compact conformational structure even though it is a linear peptide and should be a random coil. Tritium-exchange studies (39), CD (40), and NMR evidence (41, 42) now give support to this view. NMR studies with angiotensin, oxytocin, and vasopressin thus far have not indicated conformational restriction on the benzene rings, but the thin-film dialysis data are inconsistent with any conformation in which these bulky groups are extended from the otherwise compact conformation. 

Fig. 36. Computed structures of vasopressin (A) and oxytocin (B), obtained by energy minimization, starting from the -conformation (Gibson and Scheraga, 1967b). These are the first two conformations listed in Table 22. 

The procedures and calculations described in this chapter provide considerable insight into the factors affecting the conformations of polypeptides and proteins. The computer programs for gramicidin-S, oxytocin, vasopressin, etc., can also be used for larger structures—of the size of ribonuclease and lysozyme—although the required computer time is considerably increased. 

Again utilizing the NMR characterization of the /S-turn, the secondary structure of deamino oxytocin has been determined in DMSO-rfj-methanol to be the /3-type conformation indicated in Fig. 4. The handedness of the disulfide bridge is assumed to be the same in DMSO-methanol as in the aqueous system where the optical rotation studies were carried out. ... 

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