Principles of Hormone Action: The Problem of Molecular Linguistics

Hecbter, O.; Calek, A.

doi:10.1530/acta.0.077s0039

Cited by 11 publications

(7 citation statements)

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“…The present results are consistent with a previous proposal (27) Note Added in Proof. Retro-D-[D-aIle3, Gly7, malonamide9]-deaminooxytocin, a derivative where the "tail" has a carboxamide terminus similar to glycinamide in oxytocin, has now been synthesized and likewise is without biological activity (at 10-M) in the uterotonic assay.…”

Section: Resultssupporting

confidence: 94%

Contribution of the peptide backbone to the action of oxytocin analogs.

Hechter¹,

Kato²,

Nakagawa³

et al. 1975

Proc. Natl. Acad. Sci. U.S.A.

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This investigation was undertaken to evaluate the functional contribution of the peptide backbone of oxytocin in its interaction with receptor. CoreyPauling-Koltun models of [Gly7]deaminooxytocin, de-aminotocinamide, and their respective retro-D-analogs built in any specific conformation (e.g., the Walter-Urry model for oxytocin) have a quasi-equivalent topochemical arrangement of amino-acid side chains; however, the CO and NH elements of the peptide backbone of the retro-Danalog are reversed. The retro-D-analogs of deaminotocinamide and [Gly7jdeaminooxytocin (prepared using D-alle for L-Ile) and their respective N-formyl derivatives were assayed for uterotonic activity relative to related L-peptides. All retro-D-analogs (tested at concentrations ranging from 10-10 to 1O-5 M) were devoid of agonistic (or antagonistic) activity in the isolated rat uterus, except for the retro-D-[D-alle3, Gly7jdeaminooxytocinamine, which retains a terminal NH2 group on the tail; the latter is a partial agonist with very low affinity. The results obtained with retro-D-analogs indicate that one or more of the elements of the peptide backbone of the tocinamide ring are essential for "occupation" and "activation" of uterine receptors. Oxytocin action may be the resultant of multiple hydrogen-bonding interactions between CO, NH, NH2, and OH groups of the hormone with complementary groups on receptor, made possible by appropriate hydrophobic bonding.The distinctive topological arrangement of amino-acid side chains of a peptide hormone at the receptor surface is believed to be the primary determinant for those interactions that establish "occupancy" and "activation" of receptors (1). The contribution of the peptide backbone has received little attention. The fact that retro-D-analogs (2) * of certain cyclic peptides have similar biological activities as those exhibited by the parent compound (3-5) is consistent with the idea that the peptide backbone serves only as a structural scaffold for projecting amino acid side chain functionalities.t In a retro-Danalog, the "overall shape" and topochemical pattern of side chains are "quasi-equivalent" to that of a normal peptide (provided that Pro is not part of the sequence) (2-4), and differs from the normal peptide in that the CO and NH elements of the peptide bonds, as well as the amino and carboxyl termini, are reversed.If the amide elements of the backbone do not serve an important functional role in hormone action, appropriate To determine whether the CO and NH elements of the pel)-tide backbone participate in hormone interaction with receptor, we made the N-formyl derivatives of retro-D-analogs of two biologically active oxytocin analogs (6-9), deaminotocinamide and [Gly7]deaminooxytocin, which contain neither Pro nor terminal COOH or NH2 groups. The uterotonic activities of these (and related) retro-D-analogs were compared to the parent L-peptides in a rat oxytocic assay. The N-formyl derivatives of these retro-D-analogs (tested over a concentration range from 10-10 to 10-5 M) wer...

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Section: Resultssupporting

confidence: 94%

Contribution of the peptide backbone to the action of oxytocin analogs.

Hechter¹,

Kato²,

Nakagawa³

et al. 1975

Proc. Natl. Acad. Sci. U.S.A.

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“…Out of this, Menziani et al concluded that the C ‐termini of peptide ligands are ‘highly important in receptor recognition and signal transduction’ by interaction with the transmembrane binding cleft, whereas the N ‐termini ‘might bind to residues located at the entrance of the binding cleft conferring high affinity and selectivity to the peptide’35. Following the classical principle of receptor–hormone interactions via ‘address’ and ‘message’ epitopes suggested earlier49, we dissect here the sequence of native peptide ligands into four epitopes based on sequence–structure–function relationships (Table 3, Figure 1). In addition, the receptor binding sites in ET A and ET B can be delineated into four structural portions, which are complementary in shape and properties to the ligand regions (Figure 2).…”

Section: Discussionmentioning

confidence: 99%

Structural determinants for selective recognition of peptide ligands for endothelin receptor subtypes ET_A and ET_B

Lättig

Oksche

Beyermann

et al. 2009

Journal of Peptide Science

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The molecular basis for recognition of peptide ligands endothelin-1, -2 and -3 in endothelin receptors is poorly understood. Especially the origin of ligand selectivity for ET(A) or ET(B) is not clearly resolved. We derived sequence-structure-function relationships of peptides and receptors from mutational data and homology modeling. Our major findings are the dissection of peptide ligands into four epitopes and the delineation of four complementary structural portions on receptor side explaining ligand recognition in both endothelin receptor subtypes. In addition, structural determinants for ligand selectivity could be described. As a result, we could improve the selectivity of BQ3020 about 10-fold by a single amino acid substitution, validating our hypothesis for ligand selectivity caused by different entrances to the receptors' transmembrane binding sites. A narrow tunnel shape in ET(A) is restrictive for a selected group of peptide ligands' N-termini, whereas a broad funnel-shaped entrance in ET(B) accepts a variety of different shapes and properties of ligands.

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“…It is not possible here to review the principles of hormone action, (or the related problem of molecular linguistics) which develop from an examination of hormone action from a cybernetic viewpoint (for a recent treatment of the subjects, cf. Hechter and Calek, 1974).…”

Section: Energetic and Cybernetic Aspects Of Receptor Functionmentioning

confidence: 99%

“…Steroid hormones can influence genomic activity and protein synthesis in very different ways (cf. Hechter and Calek, 1974). In differentiation and development, steroids "switch" the gene program so that one gene set is "turned on" while another set is "turned off" (e.g., ecdysone in insect metamorphosis).…”

Section: Current Status Of Receptor Isolationmentioning

confidence: 99%

The Receptor Concept: Prejudice, Prediction, and Paradox

Hechter¹

1978

Advances in Experimental Medicine and Biology

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I NTRO DUCTI ONThis is a time of "great expectations" in the field of hormone and neurotransmitter action. Recent advances in our understanding of receptors have been so dramatic that we appear to be at the threshold of finally resolving the molecular nature of cellular receptors. The nature of these receptors is an important issue in biology which transcends endocrinology and neural transmission; it concerns the cardinal problem in the broad area of intercellular and intracellular communication. The once "elusive" receptors for hormones and neurotransmitters, long postulated to be the primary functional units for initiation of biological action, now appear to be "real" molecules. Specific macromolecular binding units for certain hormones and transmitters, with kinetic and specificity characteristics expected for a receptor have been reported. They can be isolated and manipulated. In several cases these receptors, derived either from the "cytosol" or solubilized from plasma membranes have been isolated in pure form. It is widely accepted that if we now follow the same strategy so successfully employed by the enzymologists (first isolate, then proceed to chemical characterization and determination of subunit sequences, conformational analysis, finally X-ray analysis) that the intimate molecular details of receptor structure and function will be clarified.If this is a period of great excitement and enthusiasm, it is also a period of great competition. Several major research groups

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Principles of Hormone Action: The Problem of Molecular Linguistics

Cited by 11 publications

References 0 publications

Contribution of the peptide backbone to the action of oxytocin analogs.

Contribution of the peptide backbone to the action of oxytocin analogs.

Structural determinants for selective recognition of peptide ligands for endothelin receptor subtypes ET_A and ET_B

The Receptor Concept: Prejudice, Prediction, and Paradox

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Principles of Hormone Action: The Problem of Molecular Linguistics

Cited by 11 publications

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Contribution of the peptide backbone to the action of oxytocin analogs.

Contribution of the peptide backbone to the action of oxytocin analogs.

Structural determinants for selective recognition of peptide ligands for endothelin receptor subtypes ETA and ETB

The Receptor Concept: Prejudice, Prediction, and Paradox

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Product

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Structural determinants for selective recognition of peptide ligands for endothelin receptor subtypes ET_A and ET_B