Abstract
Structures deposited in the Protein Data Bank (PDB) facilitate our understanding of many biological processes including those that fall under the general category of glycobiology. However, structure-based studies of how glycans affect protein structure, how they are synthesized, and how they regulate other biological processes remain challenging. Despite the abundant presence of glycans on proteins and the dense layers of glycans that surround most of our cells, structures containing glycans are underrepresented in the PDB. There are sound reasons for this, including difficulties in producing proteins with well-defined glycosylation and the tendency of mobile and heterogeneous glycans to inhibit crystallization. Nevertheless, the structures we do find in the PDB, even some of the earliest deposited structures, have had an impact on our understanding of function. I highlight a few examples in this review and point to some promises for the future. Promises include new structures from methodologies, such as cryo-EM, that are less affected by the presence of glycans and experiment-aided computational methods that build on existing structures to provide insight into the many ways glycans affect biological function.
Highlights
Glycobiology is the study of how glycans, called carbohydrates or oligosaccharides, result from, or have an impact on, a wide array of biological processes [1]
This is economical for proteins that can be expressed in bacterial cultures which synthesize all amino acids from simple substrates (e.g., 15NH4Cl and 13C-Glc), but for glycoproteins expressed in mammalian cells, which produce near-native glycosylation, this can be very expensive, and perdeuteration needed to work on larger proteins is usually not possible
They are first transferred by the action of oligosaccharide transferase (OST) enzymes as a large oligosaccharide (Glc3Man9GlcNAc2) from a dolichol pyrophosphate donor anchored to the luminal side of the endoplasmic reticulum (ER)
Summary
Structures deposited in the Protein Data Bank (PDB) facilitate our understanding of many biological processes including those that fall under the general category of glycobiology. For NMR, most structural studies depend on uniform isotope labeling with 15N and 13C This is economical for proteins that can be expressed in bacterial cultures which synthesize all amino acids from simple substrates (e.g., 15NH4Cl and 13C-Glc), but for glycoproteins expressed in mammalian cells, which produce near-native glycosylation, this can be very expensive, and perdeuteration needed to work on larger proteins is usually not possible. Since that time, these same structures have been used repeatedly to facilitate the design of new glycosylated species and rationalize their effects on efficacy of the drug. Recent examples of addition of glycans by modeling include the spike proteins of the coronavirus SARS-CoV-2, where heavy glycosylation obscures sites that might have been used for antibody development [29, 30]
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