Peptide E (a 25-amino acid peptide derived from proenkephalin A) and β-endorphin (a 31-amino acid peptide derived from proopiomelanocortin) bind with high affinity to opioid receptors and share structural similarities but induce analgesic effects of very different intensity. Indeed, whereas they possess the same N-terminus Met-enkephalin message sequence linked to a helix by a flexible spacer and a C-terminal part in random coil conformation, in contrast with peptide E, β-endorphin produces a profound analgesia. To determine the key structural elements explaining this very divergent opioid activity, we have compared the structural and pharmacological characteristics of several chimeric peptides derived from peptide E and β-endorphin. Structures were obtained under the same experimental conditions using circular dichroism, computational estimation of helical content and/or nuclear magnetic resonance spectroscopy (NMR) and NMR-restrained molecular modeling. The hot-plate and writhing tests were used in mice to evaluate the antinociceptive effects of the peptides. Our results indicate that neither the length nor the physicochemical profile of the spacer plays a fundamental role in analgesia. On the other hand, while the functional importance of the helix cannot be excluded, the last 5 residues in the C-terminal part seem to be crucial for the expression or absence of the analgesic activity of these peptides. These data raise the question of the true function of peptides E in opioidergic systems.

Urotensin II (U-II) and urotensin II-related peptide (URP) are the endogenous ligands for the orphan G-protein-coupled receptor GPR14 now renamed UT. At the periphery, U-II and/or URP exert a wide range of biological effects on cardiovascular tissues, airway smooth muscles, kidney and endocrine glands, while central administration of U-II elicits various behavioral and cardiovascular responses. There is also evidence that U-II and/or URP may be involved in a number of pathological conditions including heart failure, atherosclerosis, renal dysfunction and diabetes. Because of the potential involvement of the urotensinergic system in various physiopathological processes, there is need for the rational design of potent and selective ligands for the UT receptor. Structure–activity relationship studies have shown that the minimal sequence required to retain full biological activity is the conserved U-II(4–11) domain, in particular the Cys5 and Cys10 residues involved in the disulfide bridge, and the Phe6, Lys8 and Tyr9 residues. Free α-amino group and C-terminal COOH group are not necessary for the biological activity, and modifications of these radicals may even increase the stability of the analogs. Punctual substitution of native amino acids, notably Phe6 and Trp7, by particular residues generates analogs with antagonistic properties. These studies, which provide crucial information regarding the structural and conformational requirements for ligand–receptor interactions, will be of considerable importance for the design of novel UT ligands with increased selectivity, potency and stability, that may eventually lead to the development of innovative drugs.

Urotensin-II (U-II) is a vasoactive hormone that acts through a G-protein-coupled receptor named UT. Recently, we have shown, using the surface plasmon resonance technology that human U-II (hU-II) interacts with the hUT(281–300) fragment, a segment containing the extracellular loop III (EC-III) and short extensions of the transmembrane domains VI and VII (TM-VI and TM-VII). To further investigate the interaction of UT receptor with U-II, we have determined the solution structure of hUT(281–300) by high-resolution NMR and molecular modeling and we have examined, also using NMR, the binding with hU-II at residue level. In the presence of dodecylphosphocholine micelles, hUT(281–300) exhibited a type III β-turn (Q285–L288), followed by an α-helical structure (A289–L299), the latter including a stretch of transmembrane helix VII. Upon addition of hU-II, significant chemical shift perturbations were observed for residues located just on the N-terminal side of the β-turn (end of TM-VI/beginning of EC-III) and on one face of the α-helix (end of EC-III/beginning of TM-VII). These data, in conjunction with intermolecular NOEs, suggest that the initiation site of EC-III, as well as the upstream portion of helix VII, would be involved in agonist binding and allow to propose points of interaction in the ligand–receptor complex.

Human KIN17 is a 45-kDa eukaryotic DNA- and RNA-binding protein that plays an important role in nuclear metabolism and in particular in the general response to genotoxics. Its amino acids sequence contains a zinc finger motif (residues 28-50) within a 30-kDa N-terminal region conserved from yeast to human, and a 15-kDa C-terminal tandem of SH3-like subdomains (residues 268-393) only found in higher eukaryotes. Here we report the solution structure of the region 51-160 of human KIN17. We show that this fragment folds into a three-alpha-helix bundle packed against a three-stranded beta-sheet. It belongs to the winged helix (WH) family. Structural comparison with analogous WH domains reveals that KIN17 WH module presents an additional and highly conserved 3(10)-helix. Moreover, KIN17 WH helix H3 is not positively charged as in classical DNA-binding WH domains. Thus, human KIN17 region 51-160 might rather be involved in protein-protein interaction through its conserved surface centered on the 3(10)-helix.

Urotensin-II (U-II) and urotensin-II-related peptide (URP) are potent vasoconstrictors, and this action is mediated through a G protein-coupled receptor identified as UT. This receptor is expressed abundantly in the mammalian cardiovasculature, and the effects of U-II and URP can be blocked with urantide, a selective antagonist. Thus, we carried out a study with the aim to characterize the conformational arrangement of the three extracellular loops of UT as well as the transmembrane domains III and IV. Secondary structures of the synthetic receptor fragments were determined using circular dichroism (CD) spectroscopy in a variety of solvent and micelle conditions. Spectra showed that all receptor segments but not the extracellular loop I exhibited a propensity for adopting the alpha-helix folding. Furthermore, using surface plasmon resonance (SPR) technology, we measured the binding affinities of the ligands, U-II, URP, and urantide toward the UT extracellular segments. SPR data showed that both U-II and URP bind extracellular loops II and III with similar affinities, whereas none of these two ligands were able to interact with the extracellular loop I. Moreover, the binding of urantide was observed only with the second extracellular loop. These results imply that U-II and URP but not urantide would bind to UT according to a common pattern. Also, the correlation of the CD spectral information with the affinity data suggested that the adoption of a helical geometry in UT, by extracellular loops II and III, might be essential for favoring the binding of ligands.

Urotensin II (UII) has been described as the most potent vasoconstrictor peptide and recognized as the endogenous ligand of the orphan G protein-coupled receptor GPR14. Recently, a UII-related peptide (URP) has been isolated from the rat brain and its sequence has been established as H-Ala-Cys-Phe-Trp-Lys-Tyr-Cys-Val-OH. In order to study the structure–function relationships of URP, we have synthesized a series of URP analogs and measured their binding affinity on hGPR14-transfected cells and their contractile activity in a rat aortic ring bioassay. Alanine substitution of each residue of URP significantly reduced the binding affinity and the contractile activity of the peptides, except for the Ala8-substituted analog that retained biological activity. Most importantly, d-scan of URP revealed that [d-Trp4]URP abrogated and [d-Tyr6]URP partially suppressed the UII-evoked contractile response. [Orn5]URP, which had very low agonistic efficacy, was the most potent antagonist in this series. The solution structure of URP has been determined by 1H NMR spectroscopy and molecular dynamics. URP exhibited a single conformation characterized by an inverse γ-turn comprising residues Trp-Lys-Tyr which plays a crucial role in the biological activity of URP. These pharmacological and structural data should prove useful for the rational design of non-peptide ligands as potential GPR14 agonists and antagonists.

Determination of the effects of presenilin 1 (PSEN1) mutations, involved in autosomal dominant early-onset Alzheimer's disease (ADEOAD), on the interaction between PSEN1 and binding proteins is essential to determine which interactions are involved in Alzheimer's disease (AD) pathogenesis. The PSEN1 binding protein glycogen synthase kinase-3 beta (GSK-3 beta) has been considered as a key protein in AD pathogenesis since GSK-3 beta phosphorylates tau and hyperphosphorylated tau is a main component of neurofibrillary tangles associated to AD. We show here, using surface plasmonic resonance, that the pathogenic L392V mutation, identified in a large French ADEOAD pedigree including 39 affected members, leads to a decreased affinity to GSK-3 beta. We conclude therefore that the increase of affinity of PSEN1 to GSK-3 beta reported in previous studies is not a common effect of pathogenic mutations associated to ADEOAD.

Autosomal dominant early-onset Alzheimer's disease results mainly from mutations of the presenilin 1 (PSEN1) gene, which codes for an integral membrane protein of 467 amino acids. The hydrophilic loop (amino acids 263-407) of PSEN1, in which many pathogenic mutations have been localized, appears to be crucial for the protein function since it includes the binding domains to different PSEN1 partners. Using circular dichroism (CD) we analyzed the structural effects of the pathogenic L392V mutation and compared them with those of the E318G substitution. This study revealed that, the L392V mutation, in a phospholipidic medium which mimics the in vivo membrane environment, reduces the alpha helix content of the PSEN1 loop, whereas the E318G substitution, considered as a polymorphism, does not. These results suggest that the pathogenic effect of some PSEN1 mutations within the hydrophilic loop could be the alteration of the interaction to the different binding proteins through a disruption of the secondary structure.

Trichorzianin TA VII, Ac0 U1 A2 A3 U4 J5 Q6 U7 U8 U9 S10 L11 U12 P13 V14 U15 I16 Q17 Q18 Fol19, is a nonadecapeptide member of the peptaibol antibiotics biosynthesized by Trichoderma soil fungi, which is characterized by a high proportion of the alpha, alpha-dialkylated amino acids, alpha-aminoisobutyric acid (Aib, U) and isovaline (Iva, J), an acetylated N-terminus and a C-terminal phenylalaninol (Pheol, Fol). The main interest in such peptides stems from their ability to interact with phospholipid bilayers and form voltage-dependent transmembrane channels in planar lipid bilayers. In order to provide insights into the lipid-peptide interaction promoting the voltage gating, the conformational study of TA VII in the presence of perdeuterated sodium dodecyl sulfate (SDS-d25) micelles has been carried out. 1H sequential assignment have been performed with the use of two-dimensional homo- and -heteronuclear nmr techniques including double quantum filtered correlated spectroscopy, homonuclear Hartmann-Hahn, nuclear Overhauser effect spectroscopy, 1H-13C heteronuclear single quantum correlation, and heteronuclear multiple bond correlation. Conformational parameters, such as 3JNHC alpha H coupling constants, temperature coefficients of amide protons (delta gamma/delta TNH) and quantitative nuclear Overhauser enhancement data, lead to detailed structural information. Ninety-eight three-dimensional structures consistent with the nmr data were generated from 231 interproton distances six phi dihedral angle restraints, using restrained molecular dynamics and energy minimization calculations. The average rms deviation between the 98 refined structures and the energy-minimized average structure is 0.59 A for the backbone atoms. The structure of trichorzianin TA VII associated with SDS micelles, as determined by these methods, is characterized by two right-handed helical segments involving residues 1-8 and 11-19, linked by a beta-turn that leads to an angle about 90 degrees-100 degrees between the two helix axes; residues 18 and 19 at the end of the C-terminal helix exhibit multiple conformations.

The structure of two chiral N,N'-disubstituted-3-aminopyrrolidine lithium amides 3 and 4 in solution in THF-d(8) has been studied at low temperatures by high-field H-1, C-13, and Li-6 NMR spectroscopy. Despite their structural analogy, these two compounds adopt very different conformations in solution: while the amide 3 pyrrolidinic ring undergoes only minor changes with respect to its amino precursor 1, amide 4 presents a norbornyl-like bridged structure around Li-6(+). When excess (BuLi)-Li-6 is added to both amide solutions, 1:1 amide-(BuLi)-Li-6 complexes arise, and their structures appear, this time, very similar and organized around a parallepipedic N-Li-2-C core, the two lithium cations bridging the amide and the alkyl chain. The 4-(BuLi)-Li-6 complex appears very tight, with two distinct signals corresponding to each of the diastereotopic alpha-protons of butyllithium, by contrast with the looser 3-(BuLi)-Li-6 complex. From all these data, we propose a model to interpret the results obtained using these chiral amides in the asymmetric condensation of butyllithium with aromatic aldehydes.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTCarbanion or Enolate? A 1H, 13C, and 29Si NMR Spectroscopic AnalysisVincent Baudrillard, Gerard Ple, and Daniel DavoustCite this: J. Org. Chem. 1995, 60, 5, 1473–1474Publication Date (Print):March 1, 1995Publication History Published online1 May 2002Published inissue 1 March 1995https://pubs.acs.org/doi/10.1021/jo00110a061https://doi.org/10.1021/jo00110a061research-articleACS PublicationsRequest reuse permissionsArticle Views101Altmetric-Citations3LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts

Two new cytotoxic, nonadjacent bis-tetrahydrofuran acetogenins, cherimolin-2 and almunequin, have been isolated from the bioactive methanolic extract of Annona cherimolia seeds. In addition to these new compounds, the structure of the known acetogenins, cherimolin-1, laherradurin and otivarin (ex-dihydrocherimolin), are here revised. The structures were established by means of one- and two-dimensional NMR experiments. All compounds exhibited potent cytotoxic and antiparasitic activities.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTTrivalvone, une Nouvelle Bis-aporphine des Ecorces de Trivalvaria macrophyllaDiego Cortes, Daniel Davoust, A. Hamid A. Hadi, Saw Hla Myint, Reynald Hocquemiller, and André CavéCite this: J. Nat. Prod. 1990, 53, 4, 862–866Publication Date (Print):July 1, 1990Publication History Published online1 July 2004Published inissue 1 July 1990https://pubs.acs.org/doi/10.1021/np50070a013https://doi.org/10.1021/np50070a013research-articleACS PublicationsRequest reuse permissionsArticle Views172Altmetric-Citations9LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts

Using cytotoxicity as a bioassay guide led lo the isolation of a new aclive acetogenin from the seed of * .Murisolin.l. is the first example of a mono-tetrahydrofuran-y-lactone acelogenin with only three hydroxyl groups.Its suucture was chmcterised by mass SpectromeVy and2D homonuclear and h e m u c l e a r correlations nmr spectroscopy.The relative stereocherni~&~ of four of its six chiral centers was eslablished by I ~-n m r comparative spectral studies between the murisolin triacetaa and some bislctrahydmfuran acelogenin acetales.Annona muriciua (Annonaceae) is a fruit tree originating fmm cenual America.It is cultivated for its fruit (corossol.guanabana, soursop) in tropical and subtropical areas.The crude methanolic exmct of seeds was biologically polenl in brine shrimp tcsll and "crown gall ~m o r " ?Through fractionaling with solvenu (petroleum ether, methylcnc chloride and methanol) monitored by bioassay, followed by several steps of purification of the active extracl @etrolcum ether) involving column and thin layer chromatographies, led lo muris0lin.L a new acelogcnin.Murisolin is the third rcprescnlative of mono-teuahydrofuranic fatty y-lactone after annonacin from &na densicoma3 and goniothalamicin frorn Foniotholamus ~i-.~ ~urisolin is cytotoxic to different cell culture systems (E.D.50 < 10.l p g h l inVERO and E.D.50 < 10-3 pglml in KB) and to brine shrimp (D.L.50= 2 ppm).Several bioaclive bisleuahydrolurany-lactone acetogenins5-" have also been isolated exclusively from the Annonaceae species and recently annonacinone; isolalcd frorn Annona densicm,18 and bullalalicin isolated from -, I 9 have been described.Murisolin, 1, was isolated Crom petroleum ether extract of the seeds of Annona m w .It has been obwined in an amorphous swtc.The molecular formula, C35Ha06 has been determined by high resolution mass spectromelry (MH+:581.

ChemInformVolume 20, Issue 34 Natural Products ChemInform Abstract: Smenospondiol, a Biologically Active Hydroquinone from the Sponge Smenospongia sp. M.-L. KONDRACKI, M.-L. KONDRACKI Lab. Chim. Appl. Corps Org., CNRS, Mus. Natl. Hist. Nat., 75231 Paris, Fr.Search for more papers by this authorD. DAVOUST, D. DAVOUST Lab. Chim. Appl. Corps Org., CNRS, Mus. Natl. Hist. Nat., 75231 Paris, Fr.Search for more papers by this authorM. GUYOT, M. GUYOT Lab. Chim. Appl. Corps Org., CNRS, Mus. Natl. Hist. Nat., 75231 Paris, Fr.Search for more papers by this author M.-L. KONDRACKI, M.-L. KONDRACKI Lab. Chim. Appl. Corps Org., CNRS, Mus. Natl. Hist. Nat., 75231 Paris, Fr.Search for more papers by this authorD. DAVOUST, D. DAVOUST Lab. Chim. Appl. Corps Org., CNRS, Mus. Natl. Hist. Nat., 75231 Paris, Fr.Search for more papers by this authorM. GUYOT, M. GUYOT Lab. Chim. Appl. Corps Org., CNRS, Mus. Natl. Hist. Nat., 75231 Paris, Fr.Search for more papers by this author First published: August 22, 1989 https://doi.org/10.1002/chin.198934308Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume20, Issue34August 22, 1989 RelatedInformation