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Relation of the Conformation of Oxytocin to the Biology of Neurohypophyseal Hormones

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Relation of the Conformation of Oxytocin to the Biology of Neurohypophyseal Hormones Proc. Nat. Acad. Sci. USA Vol. 68, No. 6, pp. 1355-1359, June 1971 Relation of the Conformation of Oxytocin to the Biology of Neurohypophyseal Hormones RODERICH WALTER, I. L. SCHWARTZ, J. H. DARNELL, AND D. W. URRY* Department of Physiology, Mount Sinai School of Medicine of the City University of New York, 10 East 102 Street, New York, N.Y. 10029; Medical Research Center, Brookhaven National Laboratory, Upton, New York 11973; and * Laboratory of Molecular Biology, University of Alabama Medical Center, Birmingham, Ala. 35233 Communicated by Henry G. Kunkel, February 9, 1971 ABSTRACT The conformation of oxytocin is related the ability to generate a stimulus at optimal receptor occupa- to the evolution and to some of the biological activ- ities of neurohypophyseal hormonal peptides. On the tion (intrinsic activity). While the affinity parameter can basis of the three-dimensional structure, positions 3, 4, 7, usually be readily approximated experimentally, this cannot and 8 are the only loci at which naturally occurring neuro- be said of intrinsic activity-neither for in vivo situa- hypophyseal peptides may be expected to differ. The side tions nor for in vitro situations. In fact, we postulate that chains of these amino-acid residues are the primary de- all peptide hormones which initiate processes involving one terminants of the differential specificity in interactions between neurohypophyseal hormones and their receptors. or more coupling steps prior to a measurable response produce There are three general groups of structural modifica- levels of stimuli in excess of that which can be expressed in the tions of neurohypophyseal hormones which can be corre- measured response. The existence of such saturation phe- lated with specific changes in biological activity: (a) those nomena at any step preceding the final response has its affecting the stabilization of the backbone of the peptide, which would extensively perturb the spatial relationships biological significance in that it increases the sensitivity of the among all the constituent amino acids and hence, affect system (receptor saturation is not required for maximal both affinity and intrinsic activities uniformly; (b) those response) and protects the system from potentially deleterious which, while retaining the stability of the backbone con- fluctuations of its components. Saturation phenomena may formation, alter the steric environment and charge dis- obscure the determination true tribution of limited surface areas, and thereby can affect of the intrinsic activity of the affinity and intrinsic activity differentially; and (c) those hormone. Oneapproachbywhichthis difficulty can beovercome changing the steric and electronic requirements of moie- is by supplementing the measurement of the final biological ties comprising the active surface of the neurohypophyseal response with the measurement of a parameter that denotes peptide, without perturbing the peptide backbone of the an early step in the sequence of events-as close as possible to hormone molecule and, hence, affecting intrinsic activity without altering affinity. the initial hormone-receptor interaction. For the "biologically active" conformation of oxytocin Neurohypophyseal hormones exhibit a variety of biological ("cooperative model"), in contrast to the structure observed effects on contractile and membrane-transport phenomena. in Me2SO-MeOH (1) (or Me2SO-D2O) (3), we assume that The initial event in the action of any hormone on its target the tyrosine side-chain folds back over the 20-membered ring cell, quite independent of any intermediary events and of the component of the hormone. In placing the tyrosine side-chain nature of the final response, requires a high degree of topo- in such a conformation, we are weighing its loss of rotational logical and chemical complementarity of the hormonal freedom against (a) the reduction of the hydrophobic surface molecule and some macromolecular receptor. The elucidation area in contact with the hydrophilic environment, (b) the of the peptide backbone of oxytocin as two a-turns (1) has favorable proximity of the cross #-structure (comprised of the afforded us a point of departure for a consideration of how the hydrogen-bonded peptide N-H and C==O groups of tyrosine conformation of oxytocin can be related to the evolution of and asparagine) to the aromatic moiety of tyrosine with the neurohypophyseal hormones and, in addition, of how the possibility of a pseudo ir-ir interaction between amide groups differential biological properties of naturally occurring and aromatic ring, and (c) the possibility of intramolecular neurohypophyseal peptides and their synthetic congeners can hydrogen bonding to the CONH2 moieties of glycine, aspara- be envisioned. gine, and glutamine. Moreover, there is at present reason to The latter approach assumes that the "information" con- believe that, to a first approximation, the peptide backbone tained in the hormonal peptide finds full expression in the conformation of all known naturally occurring neurohypophy- biological parameter measured. Expressed in terms of current seal peptides (including the vasopressins) should be the same receptor theory (2), a "stimulus", generated as a consequence as that of oxytocin, although the relative population of of a hormone interacting with its specific target-tissue dis- possible rotamers of individual amino-acid side chains criminator, depends upon three factors: (a) hormone con- probably differs among different neurohypophyseal peptides. centration, (b) hormone affinity, i.e., the ability of the hor- The cooperative model of oxytocin consists of a topological mone to bind to its receptor, (c) hormone effectiveness, i.e., unit that is maximally intramolecularly stabilized. One side of the cross ,-structure, with the exception of the protruding disulfide bond and C=O of isoleucine, is essentially feature- Abbreviation: ArgVP, arginine vasopressin. less (hydrophobic surface), while the contours of the other side 1355 Downloaded by guest on October 1, 2021 1356 Medical Sciences: Walter et al. Proc. Nat. Acad. Sci. USA 68 (1971) TABLE 1. Neurohypophyseal peptides of vertebrates The side chains of residues 3, 4, 7, and 8 are the distinguishing topological features of the molecule and, as such, are the 1. Oxytocin Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2 primary determinants of the differential specificity in neuro- hypophyseal hormone-receptor interactions; however, this 2. Mesotocin - - - - Ile 3. Isotocin -SSer -Ile does not imply that all of these side chains are necessarily con- 4. Glumitocin -SSer -Gln stituents of the "active sites" of the hormone in any par- 5. Arginine ticular "hormone-receptor" complex. The specific functional vasotocin - Arg role of positions 3 and 8, for example, may be illustrated 6. Arginine by a comparison of arginine vasopressin (ArgVP), arginine vasopressin - - Phe- - - Arg vasotocin, and oxytocin. This kind of comparison has led us 7. Lysine to a unifying hypothesis for the interaction of these hormones vasopressin - Phe--- - Lys a receptors (Table to the ex- 8. Elasmobranch with number of 2)-unifying Principle I Unknown structure tent that the hormone is oriented so that its hydrophobic 9. Elasmobranch surface is in close contact with, or even in part enveloped by, a Principle II Unknown structure hydrophobic cleft on the receptor, while the opposite surface, containing the cluster of hydrophilic groups of the hormone, For phylogenetic considerations see Sawyer, W. H., in Hand- faces away from the cleft of the receptor towards the aqueous book of Experimental Pharmacology, ed. B. Berde (Springer- environment. Specifically, in the case of oxytocin, the hydro- Verlag, Berlin, 1968), Vol. 23, p. 717; and Vliegenthart, J. F. G., phobic surface will encompass the featureless surface of oxy- and D. H. S. Versteeg, J. Endocrinol., 38, 3 (1967). tocin extending from the isoleucine in position 3 to the leucine in position 8. In the case of ArgVP, the hydrophobic surface of this structure are obscured by the overlying aromatic includes phenylalanine in position 3, but excludes arginine in moiety of tyrosine, the C-terminal tripeptide, the side chain of position 8, inasmuch as the side chain of arginine will be part asparagine, and possibly the side chain of glutamine (hydro- of the hydrophilic cluster. When ArgVP interacts with the philic surface). This model utilizes each of the constituent antidiuretic receptor the arginine side chain appears to extend amino-acid residues to itsgreatest effectiveness. The side chains into the aqueous environment and hence there is no highly of each of the component amino acids-with the exception of stringent requirement for specificity at this locus. Contrari- the isoleacine, glutamine, proline, and leucine residues in wise, in view of the detrimental effect on pressor activity re- positions 3, 4, 7, and S-play a critical role in the formation sulting from stereoisomeric aminoacid replacements in posi- and intramolecular stabilization of the preferred backbone tion 8, a highly specific complementary charge interaction conformation. The side chains of residues 3, 4, 7, and 8 are free is important (Table 3). to engage in intermolecular interactions, while having a An amino acid of D-configuration in position 8 would, of limited effect on the conformation of the peptide backbone course, also change the orientation of the end peptide moiety (although bulky side chains help to stabilize the ,B-turn). On (-CONH-) of the second jo-turn (4); nevertheless,
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