Solution structure of a new hypothalamic neuropeptide, human hypocretin‐2/orexin‐B

Lee, Jung Hoon; Bang, Eunjung; Chae, Kyeong Jun; Kim, Jin Young; Lee, Dai Woon; Lee, Weontae

doi:10.1046/j.1432-1327.1999.00911.x

Cited by 73 publications

(69 citation statements)

References 38 publications

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“…A short a-helix is also present towards the peptide's C-terminal region which was not observed in orexin-A. A similar structure for orexin-B, two a-helices connected with a short linker, was also deduced in H 2 O and 30% trifluoroethanol solutions [151]. The last two amino acids (Thr and Met) in the C-terminus are unstructured in micelles and it is argued that the conformational freedom of these receptor binding residues is essential for its biological activity [52].…”

Section: Orexin Peptidesmentioning

confidence: 59%

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Recognition of GPCRs by Peptide Ligands and Membrane Compartments theory: Structural Studies of Endogenous Peptide Hormones in Membrane Environment

Sankararamakrishnan

2006

Bioscience Reports

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One of the largest family of cell surface proteins, G-protein coupled receptors (GPCRs) regulate virtually all known physiological processes in mammals. With seven transmembrane segments, they respond to diverse range of extracellular stimuli and represent a major class of drug targets. Peptidergic GPCRs use endogenous peptides as ligands. To understand the mechanism of GPCR activation and rational drug design, knowledge of threedimensional structure of receptor-ligand complex is important. The endogenous peptide hormones are often short, flexible and completely disordered in aqueous solution. According to ''Membrane Compartments Theory'', the flexible peptide binds to the membrane in the first step before it recognizes its receptor and the membrane-induced conformation is postulated to bind to the receptor in the second step. Structures of several peptide hormones have been determined in membrane-mimetic medium. In these studies, micelles, reverse micelles and bicelles have been used to mimic the cell membrane environment. Recently, conformations of two peptide hormones have also been studied in receptor-bound form. Membrane environment induces stable secondary structures in flexible peptide ligands and membrane-induced peptide structures have been correlated with their bioactivity. Results of site-directed mutagenesis, spectroscopy and other experimental studies along with the conformations determined in membrane medium have been used to interpret the role of individual residues in the peptide ligand. Structural differences of membrane-bound peptides that belong to the same family but differ in selectivity are likely to explain the mechanism of receptor selectivity and specificity of the ligands. Knowledge of peptide 3D structures in membrane environment has potential applications in rational drug design.

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Section: Orexin Peptidesmentioning

confidence: 59%

“…The absence of orexin peptides in the patient results in narcolepsy, a chronic sleep disorder [150]. Structures of both the orexin peptides have been determined in SDS micelles [52,62] as well as in solution [151].…”

Section: Orexin Peptidesmentioning

confidence: 99%

Recognition of GPCRs by Peptide Ligands and Membrane Compartments theory: Structural Studies of Endogenous Peptide Hormones in Membrane Environment

Sankararamakrishnan

2006

Bioscience Reports

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“…Therefore, the effect of this mutation is likely to affect the secondary or tertiary structure of orexin-A 14 -33 rather than the interaction with the orexin-binding site. If orexin-A, as orexin-B (Lee et al, 1999) forms an ␣-helical structure in this region, then replacement of leucine with alanine should also not have any remarkable effect on the secondary structure. Since the three-dimensional structure of orexin-A is unknown, no conclusion of its structure and the effects of mutations thereon can be made.…”

Section: Discussionmentioning

confidence: 99%

“…Although a product of a different part of the precursor peptide, orexin-B shows a 46% sequence identity with orexin-A, and these two peptide sequences seem to have arisen through duplication of a single sequence (Alvarez and Sutcliffe, 2002 which could make orexin-B an N-terminally truncated variant of orexin-A. The secondary structure of orexin-A is not known, but orexin-B has been determined to consist of two ␣-helices in 60-to 80°angles to each other (Lee et al, 1999). Orexin-A is much more lipophilic than orexin-B, and it is also more stable in blood and cerebrospinal fluid (Kastin and Akerstrom, 1999).…”

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confidence: 99%

Distinct Recognition of OX₁ and OX₂Receptors by Orexin Peptides

Ammoun¹,

Holmqvist²,

Shariatmadari³

et al. 2003

J Pharmacol Exp Ther

164

119

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In this study, we have compared the abilities of orexin-A and orexin-B and variants of orexin-A to activate different Ca 2ϩ responses (influx and release) in human OX 1 and OX 2 receptorexpressing Chinese hamster ovary cells. Responses mediated by activation of both receptor subtypes with either orexin-A or -B were primarily dependent on extracellular Ca 2ϩ , suggesting similar activation of Ca 2ϩ influx as we have previously shown for orexin-A and OX 1 receptors. Amino acid-wise truncation of orexin-A reduced its ability to activate OX 1 and OX 2 receptors, but the response mediated by the OX 2 receptor was more resistant to truncation than the response mediated by the OX 1 receptor. We also performed a sequential replacement of amino acids 14 to 26 with alanine in the truncated orexin-A variant orexin-A 14 -33 . Replacement of the same amino acids produced a fall in the potency for each receptor subtype, but the reduction was less prominent for the OX 2 receptor. The most marked reduction was produced by the replacement of Leu20, Asp25, and His26 with alanine. Interestingly, extracellular Ca 2ϩ dependence of responses to some of the mutated peptides was different from those of orexin-A and -B. The mutagenesis also suggests that although the determinants required from orexin-A for binding to and activation of the receptor are highly conserved between the orexin receptor subtypes, the OX 2 receptor requires fewer determinants. This might in part explain why orexin-B has the affinity and potency equal to orexin-A for this subtype, although it has 10-to 100-fold lower affinity and potency for the OX 1 receptor.Recently, two novel hypothalamic peptides were isolated and subsequently named orexin-A and orexin-B (Sakurai et al., 1998) or hypocretin-1 and hypocretin-2 (de Lecea et al., 1998). Despite some initial confusion, orexin-A should now be considered identical to hypocretin-1 and orexin-B to hypocretin-2. Orexins act as agonists on two G-protein-coupled receptors called OX 1 and OX 2 receptors. Increased wakefulness and reduced sleep is a well demonstrated response to central administration of orexin, and disruption of central orexinergic signaling leads to the sleep disorder narcolepsy in animal models and probably also in man (reviewed in Beuckmann and Yanagisawa, 2002;Kukkonen et al., 2002;Sutcliffe and de Lecea, 2002). The other physiological roles for orexins may be regulation of energy homeostasis and stress response, probably both via central and peripheral mechanisms (reviewed in Willie et al., 2001;Beuckmann and Yanagisawa, 2002;Kirchgessner, 2002;Kukkonen et al., 2002;Smart and Jerman, 2002).The two orexin peptides, orexin-A and -B, are both products of the same precursor peptide, preproorexin, cleavage of which results in equimolar amounts of orexin-A and orexin-B. Orexin-A is composed of 33 amino acids and it contains two disulfide bridges, whereas orexin-B is a linear peptide of 28 residues (Sakurai et al., 1998). Although a product of a different part of the precursor peptide, orexin-B sho...

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“…Mammalian orexin B is a peptide of 28 amino acids with a molecular mass of about 2.9 kDa and a C-terminal amidation. Orexin B contains two stable α-helices, as indicated by magnetic resonance imaging [59], and it shows 46% (13/28) amino acid identity to orexin A. Orexin B from rat and mouse is identical, and only one and two amino acid residues are changed in the porcine and human counterparts, respectively. Orexins have also been described in the frog Xenopus laevis and have a high similarity to the mammalian peptides [105].…”

Section: Orexin Neuropeptidesmentioning

confidence: 99%

Orexins: from neuropeptides to energy homeostasis and sleep/wake regulation

2002

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The neuropeptides orexin A and orexin B (also called hypocretin 1 and 2) were recently discovered by a "reverse pharmacology" approach as ligands for two previously orphan G protein coupled receptors: orexin receptors 1 and 2. Neurons producing orexins are located exclusively in the lateral hypothalamic area but project broadly to various parts of the brain, and they have been implicated in the control of energy homeostasis and arousal maintenance. The orexin receptors are also broadly expressed in the central nervous system. Murine and canine models suggest that defective signaling in the orexin system is responsible for the sleep/wake disorder narcolepsy. Although narcoleptic patients rarely have genetic defects in the orexin system, they lack these neuropeptides in the brain and cerebrospinal fluid, indicating that human narcolepsy is an orexin deficiency syndrome in the majority of cases. A connection between sleep/wake regulation and energy homeostasis is hypothesized with orexin neuropeptides as a molecular link.

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Solution structure of a new hypothalamic neuropeptide, human hypocretin‐2/orexin‐B

Cited by 73 publications

References 38 publications

Recognition of GPCRs by Peptide Ligands and Membrane Compartments theory: Structural Studies of Endogenous Peptide Hormones in Membrane Environment

Recognition of GPCRs by Peptide Ligands and Membrane Compartments theory: Structural Studies of Endogenous Peptide Hormones in Membrane Environment

Distinct Recognition of OX₁ and OX₂Receptors by Orexin Peptides

Orexins: from neuropeptides to energy homeostasis and sleep/wake regulation

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Solution structure of a new hypothalamic neuropeptide, human hypocretin‐2/orexin‐B

Cited by 73 publications

References 38 publications

Recognition of GPCRs by Peptide Ligands and Membrane Compartments theory: Structural Studies of Endogenous Peptide Hormones in Membrane Environment

Recognition of GPCRs by Peptide Ligands and Membrane Compartments theory: Structural Studies of Endogenous Peptide Hormones in Membrane Environment

Distinct Recognition of OX1 and OX2Receptors by Orexin Peptides

Orexins: from neuropeptides to energy homeostasis and sleep/wake regulation

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Distinct Recognition of OX₁ and OX₂Receptors by Orexin Peptides