Synthetic analogs of the hypothalamic luteinizing hormone releasing factor with increased agonist or antatonist properties

Monahan, Michael W.; Amoss, Max S.; Anderson, A-M.; Vale, Wylie

doi:10.1021/bi00747a012

Cited by 254 publications

(118 citation statements)

References 15 publications

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“…The importance of having the achiral glycine in position 6 of mammalian GnRH for biological activity was demonstrated in empirical studies three decades ago (1,11,27). Subsequent studies using N-and C-terminal-directed antibodies, fluorescence spectroscopy, molecular modeling, and NMR suggested that Gly 6 was essential to allow GnRH to assume a type IIЈ ␤-turn conformation (1, 8, 11).…”

Section: Discussionmentioning

confidence: 99%

Evolution of Constrained Gonadotropin-releasing Hormone Ligand Conformation and Receptor Selectivity

Barran

Roeske

Pawson

et al. 2005

Journal of Biological Chemistry

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Gonadotropin-releasing hormone (GnRH) is the central regulator of reproduction in vertebrates. GnRHs have recently been identified in protochordates and retain the conserved N-and C-terminal domains involved in receptor binding and activation. GnRHs of the jawed vertebrates have a central achiral amino acid (glycine) that favors a type II ␤-turn such that the N-and C-terminal domains are closely apposed in binding the GnRH receptor. However, protochordate GnRHs have a chiral amino acid in this position, suggesting that they bind their receptors in a more extended form. We demonstrate here that a protochordate GnRH receptor does not distinguish GnRHs with achiral or chiral amino acids, whereas GnRH receptors of jawed vertebrates are highly selective for GnRHs with the central achiral glycine. The poor activity of the protochordate GnRH was increased >10-fold at vertebrate receptors by replacement of the chiral amino acid with glycine or a D-amino acid, which favor the type II ␤-turn. Structural analysis of the GnRHs using ion mobility-mass spectrometry and molecular modeling showed a greater propensity for a type II ␤-turn in GnRHs with glycine or a D-amino acid, which correlates with binding affinity at vertebrate receptors. These findings indicate that the substitution of glycine for a chiral amino acid in GnRH during evolution allows a more constrained conformation for receptor binding and that this subtle single amino acid substitution in a site remote from the ligand functional domains has marked effects on its structure and activity.In vertebrates, gonadotropin-releasing hormone (GnRH) 2 is synthesized in hypothalamic neurones and conducted a few millimeters in the hypophysial portal system to the anterior pituitary, where it binds to high affinity receptors in gonadotrophs to stimulate the release of gonadotropins (1). The gonadotropins in turn stimulate hormone and gamete production by the testes and ovaries. GnRHs have also been isolated from protochordate species (2, 3) and are thought to be secreted from neurones to directly regulate the gonads (2-4) in these representatives of vertebrate progenitors. GnRHs and GnRH receptors have also been found to directly affect vertebrate gonadal function (5), possibly reflecting the earliest role of GnRH as exemplified in protochordates (6, 7). It appears, therefore, that GnRHs have an ancient evolutionary role as regulators of reproduction, first through direct neural delivery to the gonads and later as hypothalamic neuroendocrine regulators of the gonads indirectly through gonadal stimulation by gonadotropins.To date 13 structural variants of the GnRH decapeptide have been identified in vertebrates (8), 9 from protochordates, which are vertebrate progenitors (8, 9), and a 12-amino acid homolog from an octopus species (10) (Fig. 1). All of the GnRHs are characterized by the conservation of the N-terminal residues (pGlu-His-Trp-Ser) and the C-terminal residues (Pro-Gly-NH 2 ) with the exception of two conservative substitutions (Fig. 1). In cartilaginous and bon...

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Section: Discussionmentioning

confidence: 99%

Evolution of Constrained Gonadotropin-releasing Hormone Ligand Conformation and Receptor Selectivity

Barran

Roeske

Pawson

et al. 2005

Journal of Biological Chemistry

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“…1976, Schwarztein 1976. It was then rapidly discovered that positions 6 and 10 of the LHRH molecule were particularly sensitive to struc¬ tural modifications (Fugino et al 1972, Monahan et al 1973, Coy et al 1974, 1976, Rivier et al 1975): changes at these two positions, especially when made simultaneously in the same molecule, led to a marked increase in biological activity. The success of the chemistry of LHRH analogs has been particularly impressive.…”

Section: Synthesis Of Lhrh Agonistsmentioning

confidence: 99%

History of LHRH agonist and combination therapy in prostate cancer

Labrie¹,

Bélanger²,

Cusan³

et al. 1996

Endocrine Related Cancer

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“…This observation led to the suggestion that -turns may serve as sites for molecular recognition. 3,4 Moreover, turns in peptides and proteins have been frequently suggested to be the bioactive conformations [5][6][7][8][9][10][11] involved in receptor binding, immune recognition, posttranslational modifications, and other processes. 12 Since turns are the shortest relatively stable and ordered structural elements, it has been proposed that they act as nucleation sites in the process of protein folding.…”

Section: Introductionmentioning

confidence: 99%

Optical spectroscopic elucidation of β‐turns in disulfide bridged cyclic tetrapeptides

2006

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Vibrational circular dichroism (VCD) spectroscopic features of type II β‐turns were characterized previously, but, criteria for differentiation between β‐turn types had not been established yet. Model tetrapeptides, cyclized through a disulfide bridge, were designed on the basis of previous experimental results and the observed incidence of amino acid residues in the i + 1 and i + 2 positions in β‐turns, to determine the features of VCD spectra of type I and II β‐turns. The results were correlated with electronic circular dichroism (ECD) spectra and VCD spectra calculated from conformational data obtained by molecular dynamics (MD) simulations. All cyclic tetrapeptides yielded VCD signals with a higher frequency negative and a lower frequency positive couplet with negative lobes overlapping. MD simulations confirmed the conformational homogeneity of these peptides in solution. Comparison with ECD spectroscopy, MD, and quantum chemical calculation results suggested that the low frequency component of VCD spectra originating from the tertiary amide vibrations could be used to distinguish between types of β‐turn structures. On the basis of this observation, VCD spectroscopic features of type II and VIII β‐turns and ECD spectroscopic properties of a type VIII β‐turn were suggested. The need for independent experimental as well as theoretical investigations to obtain decisive conformational information was recognized. © 2006 Wiley Periodicals, Inc. Biopolymers 85: 1–11, 2007.This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

show abstract

Synthetic analogs of the hypothalamic luteinizing hormone releasing factor with increased agonist or antatonist properties

Cited by 254 publications

References 15 publications

Evolution of Constrained Gonadotropin-releasing Hormone Ligand Conformation and Receptor Selectivity

Evolution of Constrained Gonadotropin-releasing Hormone Ligand Conformation and Receptor Selectivity

History of LHRH agonist and combination therapy in prostate cancer

Optical spectroscopic elucidation of β‐turns in disulfide bridged cyclic tetrapeptides

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