O‐Linked glycopeptides retain helicity in water

Palian, Michael M.; Jacobsen, Neil E.; Polt, Robin

doi:10.1034/j.1399-3011.2001.00906.x

Cited by 12 publications

(8 citation statements)

References 64 publications

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“…For a 17-mer sequence quite unrelated to mucins, with a single isolated mannosylated serine residue, others have shown that glycosylation has only a very modest impact on the conformational tendencies of the peptide backbone. 32 Additionally, glycosylation at a single site with GalNAc in a sequence from LI-Cadherin has a notable conformational influence. 33 While in a-dystroglycan important physiological functions rest with the mannose-based tetrasaccharides that occupy some of the sites, our results support the contention that in this region of clustered glycosylation, the GalNAc-linked glycans at other sites are important in stabilizing the structure, and thereby contribute to the proper display and intermolecular interactions of the mannosebased tetrasaccharides.…”

Section: Discussionmentioning

confidence: 99%

Conformational consequences of protein glycosylation: Preparation of O‐mannosyl serine and threonine building blocks, and their incorporation into glycopeptide sequences derived from α‐dystroglycan

et al. 2008

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With the goal to investigate the structural impact of O‐mannosyl glycosylation on α‐dystroglycan, a glycoprotein that has an important role in the extracellular organization of muscle, glycopeptides derived from its mucin‐like sequence have been prepared by solid‐phase peptide synthesis. Two approaches have been explored to obtain needed mannosylated serine and threonine building blocks. With the α‐carboxyl group unprotected, and with tetraaceto‐1‐fluoro‐α‐D‐mannose as the sugar donor, the desired α‐O‐mannosyl‐Fmoc‐Ser/Thr formed, along with mannosyl ester isomers and the species with mannose attached to both hydroxyl and carboxyl functions. Relevant mechanistic questions and stability issues were elucidated. Alternatively, building blocks were made with the α‐carboxyl protected/activated as the pentafluorophenyl (Pfp) ester. Glycopeptides synthesized herein contained 5–9 residues, and featured one, two, and four consecutive Ser and/or Thr residues O‐glycosylated with mannose. Circular dichroism (CD) spectra for Man‐containing glycopeptides recorded in water show them to be not well ordered. For one of the α‐dystroglycan‐derived sequences, the comparative conformational consequences of glycosylation by either Man or GalNAc have been examined by CD and NMR, with both methods showing a more organized structure when GalNAc is present. © 2007 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 90: 358–368, 2008.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

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Section: Discussionmentioning

confidence: 99%

Conformational consequences of protein glycosylation: Preparation of O‐mannosyl serine and threonine building blocks, and their incorporation into glycopeptide sequences derived from α‐dystroglycan

et al. 2008

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“…It is well known that O-glycosylation of Ser and Thr has a profound effect on the conformation of the underlying peptide backbone, 50 however, such effect may be context dependent. 51,52 This effect also regulates the 3D-orientation of the sugar attached to Ser or Thr, and therefore, the study of the bioactive conformation of a given glycopeptide obviously requires the careful analysis of both the conformation of the peptide backbone and the orientation of the sugar. Thus, 3D models of the glycopeptides were built employing the experimental NMR data by using a standard protocol of combined automated NOE assignment and structure calculations employing the CYANA program 53 (see S.I., Table S9, for the statistics of the NMR solution structures of the N/OFQ peptide and glycopeptides 1-3).…”

Section: Glycopeptide Modelingmentioning

confidence: 99%

Synthesis, biological evaluation and structural characterization of novel glycopeptide analogues of nociceptin N/OFQ

et al. 2011

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To examine if the biological activity of the N/OFQ peptide, which is the native ligand of the pain-related and viable drug target NOP receptor, could be modulated by glycosylation and if such effects could be conformationally related, we have synthesized three N/OFQ glycopeptide analogues, namely: [Thr(5)-O-α-D-GalNAc-N/OFQ] (glycopeptide 1), [Ser(10)-O-α-D-GalNAc]-N/OFQ (glycopeptide 2) and [Ser(10)-O-β-D-GlcNAc]-N/OFQ] (glycopeptide 3). They were tested for biological activity in competition binding assays using the zebrafish animal model in which glycopeptide 2 exhibited a slightly improved binding affinity, whereas glycopeptide 1 showed a remarkably reduced binding affinity compared to the parent compound and glycopeptide 3. The structural analysis of these glycopeptides and the parent N/OFQ peptide by NMR and circular dichroism indicated that their aqueous solutions are mainly populated by random coil conformers. However, in membrane mimic environments a certain proportion of the molecules of all these peptides exist as α-helix structures. Interestingly, under these experimental conditions, glycopeptide 1 (glycosylated at Thr-5) exhibited a population of folded hairpin-like geometries. From these facts it is tempting to speculate that nociceptin analogues showing linear helical structures are more complementary and thus interact more efficiently with the native NOP receptor than folded structures, since glycopeptide 1 showed a significantly reduced binding affinity for the NOP receptor.

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“…Contradictory results have been found for the effect of O-glycosylation on peptide stability. While O-glycosylation can increase the stability of helices in peptides (Palian et al, 2001), there are also studies that have reported a destabilizing effect of O-glycosylation on some peptides (Vijayalekshmi et al, 2003;Spiriti et al, 2008).…”

Section: Influence Of Glycosylation On Protein Folding and Conformationmentioning

confidence: 99%

Analysis and validation of carbohydrate three-dimensional structures

Lütteke

2009

Acta Crystallogr D Biol Cryst

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Knowledge of the three-dimensional structures of the carbohydrate molecules is indispensable for a full understanding of the molecular processes in which carbohydrates are involved, such as protein glycosylation or protein-carbohydrate interactions. The Protein Data Bank (PDB) is a valuable resource for three-dimensional structural information on glycoproteins and protein-carbohydrate complexes. Unfortunately, many carbohydrate moieties in the PDB contain inconsistencies or errors. This article gives an overview of the information that can be obtained from individual PDB entries and from statistical analyses of sets of three-dimensional structures, of typical problems that arise during the analysis of carbohydrate three-dimensional structures and of the validation tools that are currently available to scientists to evaluate the quality of these structures.

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O‐Linked glycopeptides retain helicity in water

Cited by 12 publications

References 64 publications

Conformational consequences of protein glycosylation: Preparation of O‐mannosyl serine and threonine building blocks, and their incorporation into glycopeptide sequences derived from α‐dystroglycan

Conformational consequences of protein glycosylation: Preparation of O‐mannosyl serine and threonine building blocks, and their incorporation into glycopeptide sequences derived from α‐dystroglycan

Synthesis, biological evaluation and structural characterization of novel glycopeptide analogues of nociceptin N/OFQ

Analysis and validation of carbohydrate three-dimensional structures

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