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Chem Biol Drug Des 2008; 72: 455–482
Review Article

ª 2008 The Authors Journal compilation ª 2008 Blackwell Munksgaard doi: 10.1111/j.1747-0285.2008.00741.x

The Structure of Glycosaminoglycans and their Interactions with Proteins
Neha S. Gandhi1,2 and Ricardo L. Mancera1,2,3,*

Western Australian Biomedical Research Institute, Curtin University of Technology, GPO Box U1987, Perth, WA6845, Australia 2 School of Biomedical Sciences, Curtin University of Technology, GPO Box U1987, Perth, WA 6845, Australia 3 School of Pharmacy, Curtin University of Technology, GPO Box U1987, Perth, WA 6845, Australia *Corresponding author: Ricardo L. Mancera
Glycosaminoglycans (GAGs) are important complex carbohydrates that participate in many biological processesthrough the regulation of their various protein partners. Biochemical, structural biology and molecular modelling approaches have assisted in understanding the molecular basis of such interactions, creating an opportunity to capitalize on the large structural diversity of GAGs in the discovery of new drugs. The complexity of GAG–protein interactions is in part due to the conformational flexibility andunderlying sulphation patterns of GAGs, the role of metal ions and the effect of pH on the affinity of binding. Current understanding of the structure of GAGs and their interactions with proteins is here reviewed: the basic structures and functions of GAGs and their proteoglycans, their clinical significance, the three-dimensional features of GAGs, their interactions with proteins and the molecularmodelling of heparin binding sites and GAG–protein interactions. This review focuses on some key aspects of GAG structure–function relationships using classical examples that illustrate the specificity of GAG–protein interactions, such as growth factors, anti-thrombin, cytokines and cell adhesion molecules. New approaches to the development of GAG mimetics as possible new glycotherapeutics are alsobriefly covered. Key words: carbohydrates, chondroitin sulphate, dermatan sulphate, glycosaminoglycans, heparan sulphate, heparin, hyaluronic acid, keratan sulphate, proteoglycans Received 17 September 2008, revised and accepted for publication 19 October 2008

in cell–cell and cell–matrix interactions that are crucial to the development and function of complex multicellular organisms. Glycomictechnologies for exploring the structure of complex sugar molecules have emerged in the past two decades, opening up a new frontier which has been called 'glycobiology' (1). This review provides an introduction to the structural properties of the linear chain glycans called glycosaminoglycans (GAGs) and their interactions with proteins.

Basic Features and Functions of GAGs
Glycosaminoglycansare large complex carbohydrate molecules that interact with a wide range of proteins involved in physiological and pathological processes (2,3). Glycosaminoglycans are sometimes known as mucopolysaccharides because of their viscous, lubricating properties, as found in mucous secretions. These molecules are present on all animal cell surfaces in the extracellular matrix (ECM), and some are known tobind and regulate a number of distinct proteins, including chemokines, cytokines, growth factors, morphogens, enzymes and adhesion molecules (2,4). The key properties of GAGs are summarized in Table 1. Glycosaminoglycans in aqueous solution are surrounded by a shell of water molecules, which makes them occupy an enormous hydrodynamic volume in solution (5). When a solution of GAGs is compressed,the water is squeezed out and the GAGs are forced to occupy a smaller volume. When the compression is removed, GAGs regain their original hydrated volume because of the repulsion arising from their negative charges (5). Classification of GAGs Glycosaminoglycans are linear, sulphated, negatively charged polysaccharides that have molecular weights of roughly 10–100 kDa. There are two main types of...
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