Dissecting the conformation of glycans and their interactions with proteins
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(2020) 27:93
REVIEW
Open Access
Dissecting the conformation of glycans and their interactions with proteins Sheng-Hung Wang1, Tsai-Jung Wu1, Chien-Wei Lee1 and John Yu1,2*
Abstract The use of in silico strategies to develop the structural basis for a rational optimization of glycan-protein interactions remains a great challenge. This problem derives, in part, from the lack of technologies to quantitatively and qualitatively assess the complex assembling between a glycan and the targeted protein molecule. Since there is an unmet need for developing new sugar-targeted therapeutics, many investigators are searching for technology platforms to elucidate various types of molecular interactions within glycan-protein complexes and aid in the development of glycan-targeted therapies. Here we discuss three important technology platforms commonly used in the assessment of the complex assembly of glycosylated biomolecules, such as glycoproteins or glycosphingolipids: Biacore analysis, molecular docking, and molecular dynamics simulations. We will also discuss the structural investigation of glycosylated biomolecules, including conformational changes of glycans and their impact on molecular interactions within the glycan-protein complex. For glycoproteins, secreted protein acidic and rich in cysteine (SPARC), which is associated with various lung disorders, such as chronic obstructive pulmonary disease (COPD) and lung cancer, will be taken as an example showing that the core fucosylation of N-glycan in SPARC regulates protein-binding affinity with extracellular matrix collagen. For glycosphingolipids (GSLs), Globo H ceramide, an important tumor-associated GSL which is being actively investigated as a target for new cancer immunotherapies, will be used to demonstrate how glycan structure plays a significant role in enhancing angiogenesis in tumor microenvironments. Keywords: Glycan, Glycosphingolipid, Conformational changes, SPARC, Globo H Ceramide, Molecular modeling, Biacore, Molecular docking, Molecular dynamics
Introduction Aberrant expression of sugar is a unique feature of cancer cells [8, 18, 25, 29, 73]. In this rapidly advancing era of anticancer therapeutics, most of the available therapeutics are directed against proteins/glycoproteins. The profile of glycans expressed on cell surface are correlated with cell types; for example, specific sugar signatures of cancer cells were observed [18, 72, 73]. Therefore, glycans are used as targets of therapeutic development because their expressions and the conformations required * Correspondence: [email protected] 1 Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, and Chang Gung University, Taoyuan 333, Taiwan 2 Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
for molecular recognition in cancer are usually unique [18, 72, 73]. Compared with traditional small molecule anticancer drugs, the structural basis for therapeutic design in the targeting of sugar-protein complexes for clinical us
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