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Abstract

Complex glycans that are located at the surface of cells, deposited in the extracellular matrix and attached to soluble signalling molecules have a crucial role in the phenotypic expression of cellular genotypes. However, owing to their structural complexity and some redundancy in terms of structures that elicit a function, the therapeutic potential of complex glycans has not been well exploited, with a few notable exceptions. This review outlines recent advances that promise to increase our ability to use complex glycans as therapeutics. Opportunities for the development of further structure-function relationships for these complex molecules are also discussed.

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Glycosylation and the immune system.

P M Rudd, T. Elliott, P. Cresswell … (2001)

Almost all of the key molecules involved in the innate and adaptive immune response are glycoproteins. In the cellular immune system, specific glycoforms are involved in the folding, quality control, and assembly of peptide-loaded major histocompatibility complex (MHC) antigens and the T cell receptor complex. Although some glycopeptide antigens are presented by the MHC, the generation of peptide antigens from glycoproteins may require enzymatic removal of sugars before the protein can be cleaved. Oligosaccharides attached to glycoproteins in the junction between T cells and antigen-presenting cells help to orient binding faces, provide protease protection, and restrict nonspecific lateral protein-protein interactions. In the humoral immune system, all of the immunoglobulins and most of the complement components are glycosylated. Although a major function for sugars is to contribute to the stability of the proteins to which they are attached, specific glycoforms are involved in recognition events. For example, in rheumatoid arthritis, an autoimmune disease, agalactosylated glycoforms of aggregated immunoglobulin G may induce association with the mannose-binding lectin and contribute to the pathology.

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Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization.

J Schlessinger, A Plotnikov, O. Ibrahimi … (2000)

The crystal structure of a dimeric 2:2:2 FGF:FGFR:heparin ternary complex at 3 A resolution has been determined. Within each 1:1 FGF:FGFR complex, heparin makes numerous contacts with both FGF and FGFR, thereby augmenting FGF-FGFR binding. Heparin also interacts with FGFR in the adjoining 1:1 FGF:FGFR complex to promote FGFR dimerization. The 6-O-sulfate group of heparin plays a pivotal role in mediating both interactions. The unexpected stoichiometry of heparin binding in the structure led us to propose a revised model for FGFR dimerization. Biochemical data in support of this model are also presented. This model provides a structural basis for FGFR activation by small molecule heparin analogs and may facilitate the design of heparin mimetics capable of modulating FGF signaling.

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Incorporation of azides into recombinant proteins for chemoselective modification by the Staudinger ligation.

Kristi Kiick, Eliana Saxon, David Tirrell … (2002)

The introduction of chemically unique groups into proteins by means of non-natural amino acids has numerous applications in protein engineering and functional studies. One method to achieve this involves the utilization of a non-natural amino acid by the cell's native translational apparatus. Here we demonstrate that a methionine surrogate, azidohomoalanine, is activated by the methionyl-tRNA synthetase of Escherichia coli and replaces methionine in proteins expressed in methionine-depleted bacterial cultures. We further show that proteins containing azidohomoalanine can be selectively modified in the presence of other cellular proteins by means of Staudinger ligation with triarylphosphine reagents. Incorporation of azide-functionalized amino acids into proteins in vivo provides opportunities for protein modification under native conditions and selective labeling of proteins in the intracellular environment.

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PubMed ID:: 15459677

DOI:: 10.1038/nrd1521

ScienceOpen disciplines: Chemistry

Keywords: Animals,Drug Industry,methods,trends,Humans,Polysaccharides,chemistry,therapeutic use,Structure-Activity Relationship,Thrombosis,drug therapy

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ScienceOpen disciplines: Chemistry

Keywords: Animals, Drug Industry, methods, trends, Humans, Polysaccharides, chemistry, therapeutic use, Structure-Activity Relationship, Thrombosis, drug therapy

Glycomics: a pathway to a class of new and improved therapeutics.

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Most cited references 69

Glycosylation and the immune system.

Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization.

Incorporation of azides into recombinant proteins for chemoselective modification by the Staudinger ligation.

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