Conformation of cyclo(L-alanylglycyl-.epsilon.-aminocaproyl), a cyclized dipeptide model for a .beta. bend. 2. Synthesis, nuclear magnetic resonance, and circular dichroism measurements

Deslauriers, R.; Evans, David J.; Leach, Sydney; Meinwald, Yvonne C.; Minasian, E.; Némethy, George; Rae, Ian D.; Scheraga, Harold A.; Somorjai, R. L.

doi:10.1021/ma50005a017

Cited by 45 publications

(17 citation statements)

References 13 publications

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“…The distinctive a-helix-like "class C" CD spectrum (Fig. 2) obtained from cyclo[Asn']LPK in aqueous solution indicates either a type I or a type II' /-turn in small cyclic peptides (13,24,25). NMR showed a strong NOE connectivity between the backbone amide protons of Asn-1 and Leu-8, confirming that the molecule was cyclic.…”

mentioning

confidence: 93%

Active conformation of an insect neuropeptide family.

Nachman

Roberts

Dyson

et al. 1991

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

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To understand the structural and chemical basis for insect neuropeptide activity, we have designed, synthesized, and determined the conformation of a biologically active cyclic analog of the pyrokinins, an insect neuropeptide family that mediates myotropic (visceral muscle contractile) activity. Members of this insect neuropeptide family share the common C-terminal pentapeptide sequence Phe-Xaa-Pro-ArgLeu-NH2 (Xaa = Ser, Thr, or Val). Circular dichroic, nuclear magnetic resonance, and molecular dynamics analyses of the conformationally restricted cyclic pyrokinin analog cydo(-AsnThr-Ser-Phe-Thr-Pro-Arg-Leu-) indicated the presence of a (-turn in the active core region encompassing residues ThrPro-Arg-Leu. The rigid cyclic analog retains biological activity, suggesting that its C-terminal (3-turn is the active pyrokinin conformation recognized by the myotropic receptor. As individual pyrokinins and pyrokinin-like neuropeptides demonstrate both oviduct-contractile and pheromone-biosynthesis activities in various insects, the biologically active (-turn structure reported here holds broad significance for many biological processes.Insect neuropeptides mediate many critical processes such as pheromone production, diuresis, visceral muscle contraction (myotropic activity), blood sugar level, mating, and pupal development (1). Yet, a complete characterization of these biologically active peptides has proved extremely difficult. Nearly six decades passed between the first investigations into the role of neuropeptide hormones in insect physiology by Kopec in 1917 (2) and the first report of the isolation and sequence analysis of an insect neuropeptide in 1975 (3). Moreover, despite the large number of insect neuropeptides that have been identified since then, no active conformation of an insect neuropeptide or analog has yet been determined.The pyrokinin insect neuropeptides are particularly suitable for complete characterization because they stimulate contractions of cockroach proctodeum (hindgut) and oviduct, and their myotropic activity can be readily tested with the isolated hindgut bioassay (4), which is both rapid and reproducible. Leucopyrokinin (LPK), pGlu-Thr-Ser-PheThr-Pro-Arg-Leu-NH2, is isolated from heads of the Madeira cockroach (Leucophaea maderae) (4), where it is found in the corpora cardiaca, a neurosecretory organ analogous to the pituitary and hypothalamus glands of the vertebrate endocrine system. Three related neuropeptides from the locust are more potent stimulators of oviduct than hindgut contraction (5,6). In this paper, we report the active conformation of a cyclic pyrokinin analog determined by both experimental and computational techniques. The tight constraints on the active core structure of this cyclized peptide, which maintains biological activity despite its relative rigidity, suggest that this is the conformation recognized by the myotropic receptor. The rational approach to peptide design used here has proved useful for other peptide ligands (7). The fragment Thr-Ser-Phe-Thr-Pr...

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mentioning

confidence: 93%

Active conformation of an insect neuropeptide family.

Nachman

Roberts

Dyson

et al. 1991

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

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“…The latter peptides are considered to be in a disordered form due to a characteristic negative band below 210 nm. 19 How-ever, the spectrum of Boc-Phe-Pro-Asn-AlaThr-NHMe may support the presence of some ordered structures in this peptide in aqueous solution. The positive band at 224nm may be…”

Section: Circular Dichroic Studymentioning

confidence: 92%

Conformational Aspects of Boc–Phe–Pro–Asn–Ala–Thr–NHMe; A Model of a N-Glycosylation Site in Ovomucoid

Maeji

Ishii

Inoue

et al. 1986

Polym J

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ABSTRACT:A peptide sequence (Boc-Phe-Pro-Asn-Ala-Thr-NHMe) corresponding to one of the N-glycosylation sites in hen egg ovomucoid was studied with its related fragment analogues, Boc-Pro-Asn-Ala-Thr-NHMe, Boc-Asn-Ala-Thr-NHMe, and Boc-Ala-Thr-NHMe by NMR and CD to investigate their backbone conformations and possible intramolecular interactions. From the CD study, Boc-Phe-Pro-Asn-Ala-Thr-NHMe may adopt some ordered structures in aqueous solution. However, in this peptide series, there is no stable hydrogen bonds involving backbone amide protons nor is there any definitive evidence for intramolecular hydrogen bonds involving Asn and Thr side chains. But, it is evident from the temperature study of chemical shifts that the hydrogen bonding tendency of the Thr hydroxyl protons and the Asn carboxyamide protons is dependent on both the triplet sequence and chain length of the peptide analogues. The potential to form some kind of loop structure rather than the presence of some stable secondary structure is indicated.

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“…The Aca linker was first carefully investigated in peptides by Scheraga, Woody, and coworkers, who sought to establish spectroscopic parameters for ß-turns in peptides and proteins [52][53][54][55]. Because open-chain peptides are flexible and exist as a mixture of conformations in solution, small, cyclic peptides seemed to be an ideal model system.…”

Section: The Aca Tethermentioning

confidence: 99%

“…Since peptides are flexible in solution, spectral analysis of ß-turn types were previously determined by correlating data from CD, NMR, and molecular dynamics [57]. The development of the Acacyclized ß-turn mimics provided more conformationally biased templates for CD analysis [52,53]. The macrocycles are often referenced as standards for type I and II ß-turns [58].…”

Section: 5-dimethyi Acamentioning

confidence: 99%

Synthesis, Conformational Analysis, and Biological Activity of Proposed Vitronectin Antagonists

Katz¹,

Aubé²

2001

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Conformation of cyclo(L-alanylglycyl-.epsilon.-aminocaproyl), a cyclized dipeptide model for a .beta. bend. 2. Synthesis, nuclear magnetic resonance, and circular dichroism measurements

Cited by 45 publications

References 13 publications

Active conformation of an insect neuropeptide family.

Active conformation of an insect neuropeptide family.

Conformational Aspects of Boc–Phe–Pro–Asn–Ala–Thr–NHMe; A Model of a N-Glycosylation Site in Ovomucoid

Synthesis, Conformational Analysis, and Biological Activity of Proposed Vitronectin Antagonists

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