Chemistry-driven glycoscience Kiessling, Laura L.
Bioorganic & medicinal chemistry,
10/2018, Letnik:
26, Številka:
19
Journal Article
Recenzirano
Carbohydrates are the most prominent features of the cell’s exterior—they are the cell’s “face” and serve as the cell’s identification card. The features of cell surface glycans (e.g. glycoproteins, ...glycolipids, polysaccharides) can be read by proteins, other cells, or organisms. In all of these contexts, glycan-binding proteins typically recognize (“read”) glycan identity. This recognition mediates important host-microbe interactions, as well as critical physiological functions, including fertilization, development, and immune system function. This article focuses on how proteins recognize glycans with an emphasis on three objectives: 1) to understand the molecular basis for carbohydrate recognition, 2) to implement that understanding to develop functional probes of protein-carbohydrate interactions, and 3) to apply those probes to elucidate and exploit the physiological consequences of protein–carbohydrate interactions. In this context, our group has focused on two key aspects of carbohydrate recognition: CH-π and multivalent interactions. We are applying the foundational knowledge gained from our studies for purposes ranging from illuminating host-microbe interactions to probing immune system function.
Chemical Glycobiology Bertozzi, Carolyn R.; Kiessling, Laura L.
Science (American Association for the Advancement of Science),
03/2001, Letnik:
291, Številka:
5512
Journal Article
Recenzirano
Chemical tools have proven indispensable for studies in glycobiology. Synthetic oligosaccharides and glycoconjugates provide materials for correlating structure with function. Synthetic mimics of the ...complex assemblies found on cell surfaces can modulate cellular interactions and are under development as therapeutic agents. Small molecule inhibitors of carbohydrate biosynthetic and processing enzymes can block the assembly of specific oligosaccharide structures. Inhibitors of carbohydrate recognition and biosynthesis can reveal the biological functions of the carbohydrate epitope and its cognate receptors. Carbohydrate biosynthetic pathways are often amenable to interception with synthetic unnatural substrates. Such metabolic interference can block the expression of oligosaccharides or alter the structures of the sugars presented on cells. Collectively, these chemical approaches are contributing great insight into the myriad biological functions of oligosaccharides.
Carbohydrate–Aromatic Interactions in Proteins Hudson, Kieran L; Bartlett, Gail J; Diehl, Roger C ...
Journal of the American Chemical Society,
12/2015, Letnik:
137, Številka:
48
Journal Article
Recenzirano
Odprti dostop
Protein–carbohydrate interactions play pivotal roles in health and disease. However, defining and manipulating these interactions has been hindered by an incomplete understanding of the underlying ...fundamental forces. To elucidate common and discriminating features in carbohydrate recognition, we have analyzed quantitatively X-ray crystal structures of proteins with noncovalently bound carbohydrates. Within the carbohydrate-binding pockets, aliphatic hydrophobic residues are disfavored, whereas aromatic side chains are enriched. The greatest preference is for tryptophan with an increased prevalence of 9-fold. Variations in the spatial orientation of amino acids around different monosaccharides indicate specific carbohydrate C–H bonds interact preferentially with aromatic residues. These preferences are consistent with the electronic properties of both the carbohydrate C–H bonds and the aromatic residues. Those carbohydrates that present patches of electropositive saccharide C–H bonds engage more often in CH−π interactions involving electron-rich aromatic partners. These electronic effects are also manifested when carbohydrate–aromatic interactions are monitored in solution: NMR analysis indicates that indole favorably binds to electron-poor C–H bonds of model carbohydrates, and a clear linear free energy relationships with substituted indoles supports the importance of complementary electronic effects in driving protein–carbohydrate interactions. Together, our data indicate that electrostatic and electronic complementarity between carbohydrates and aromatic residues play key roles in driving protein–carbohydrate complexation. Moreover, these weak noncovalent interactions influence which saccharide residues bind to proteins, and how they are positioned within carbohydrate-binding sites.
Cell‐surface receptors acquire information from the extracellular environment and coordinate intracellular responses. Many receptors do not operate as individual entities, but rather as part of ...dimeric or oligomeric complexes. Coupling the functions of multiple receptors may endow signaling pathways with the sensitivity and malleability required to govern cellular responses. Moreover, multireceptor signaling complexes may provide a means of spatially segregating otherwise degenerate signaling cascades. Understanding the mechanisms, extent, and consequences of receptor co‐localization and interreceptor communication is critical; chemical synthesis can provide compounds to address the role of receptor assembly in signal transduction. Multivalent ligands can be generated that possess a variety of sizes, shapes, valencies, orientations, and densities of binding elements. This Review focuses on the use of synthetic multivalent ligands to characterize receptor function.
Receptors at the cell surface function within the context of highly organized multiprotein complexes. However, the mechanisms by which these receptors process, amplify, and integrate sensory information are unclear. Synthetic multivalent ligands with diverse structures can be used to reveal fundamental information for the elucidation of regulatory features in receptor systems.
Glycans are key participants in biological processes ranging from reproduction to cellular communication to infection. Revealing glycan roles and the underlying molecular mechanisms by which glycans ...manifest their function requires access to glycan derivatives that vary systematically. To this end, glycopolymers (polymers bearing pendant carbohydrates) have emerged as valuable glycan analogs. Because glycopolymers can readily be synthesized, their overall shape can be varied, and they can be altered systematically to dissect the structural features that underpin their activities. This review provides examples in which glycopolymers have been used to effect carbohydrate-mediated signal transduction. Our objective is to illustrate how these powerful tools can reveal the molecular mechanisms that underlie carbohydrate-mediated signal transduction.
Chemical approaches to glycobiology Kiessling, Laura L; Splain, Rebecca A
Annual review of biochemistry,
01/2010, Letnik:
79, Številka:
1
Journal Article
Recenzirano
Glycans are ubiquitous components of all organisms. Efforts to elucidate glycan function and to understand how they are assembled and disassembled can reap benefits in fields ranging from bioenergy ...to human medicine. Significant advances in our knowledge of glycan biosynthesis and function are emerging, and chemical biology approaches are accelerating the pace of discovery. Novel strategies for assembling oligosaccharides, glycoproteins, and other glycoconjugates are providing access to critical materials for interrogating glycan function. Chemoselective reactions that facilitate the synthesis of glycan-substituted imaging agents, arrays, and materials are yielding compounds to interrogate and perturb glycan function and dysfunction. To complement these advances, small molecules are being generated that inhibit key glycan-binding proteins or biosynthetic enzymes. These examples illustrate how chemical glycobiology is providing new insight into the functional roles of glycans and new opportunities to interfere with or exploit these roles.
Carbohydrate recognition is crucial for biological processes ranging from development to immune system function to host–pathogen interactions. The proteins that bind glycans are faced with a daunting ...task: to coax these hydrophilic species out of water and into a binding site. Here, we examine the forces underlying glycan recognition by proteins. Our previous bioinformatic study of glycan-binding sites indicated that the most overrepresented side chains are electron-rich aromatic residues, including tyrosine and tryptophan. These findings point to the importance of CH−π interactions for glycan binding. Studies of CH−π interactions show a strong dependence on the presence of an electron-rich π system, and the data indicate binding is enhanced by complementary electronic interactions between the electron-rich aromatic ring and the partial positive charge of the carbohydrate C–H protons. This electronic dependence means that carbohydrate residues with multiple aligned highly polarized C–H bonds, such as β-galactose, form strong CH−π interactions, whereas less polarized residues such as α-mannose do not. This information can guide the design of proteins to recognize sugars and the generation of ligands for proteins, small molecules, or catalysts that bind sugars.
Recent advances in chemical proteomics have begun to characterize the reactivity and ligandability of lysines on a global scale. Yet, only a limited diversity of aminophilic electrophiles have been ...evaluated for interactions with the lysine proteome. Here, we report an in-depth profiling of >30 uncharted aminophilic chemotypes that greatly expands the content of ligandable lysines in human proteins. Aminophilic electrophiles showed disparate proteomic reactivities that range from selective interactions with a handful of lysines to, for a set of dicarboxaldehyde fragments, remarkably broad engagement of the covalent small-molecule-lysine interactions captured by the entire library. We used these latter 'scout' electrophiles to efficiently map ligandable lysines in primary human immune cells under stimulatory conditions. Finally, we show that aminophilic compounds perturb diverse biochemical functions through site-selective modification of lysines in proteins, including protein-RNA interactions implicated in innate immune responses. These findings support the broad potential of covalent chemistry for targeting functional lysines in the human proteome.
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•Elucidating lectin selectivity for microbial glycans could yield new antibiotic strategies.•Microbe-binding lectins can bind an unexpectedly wide range of glycan epitopes.•Mammalian ...microbe-binding lectins are oligomeric or form oligomers upon binding.•Expanding glycan microarray composition is critical for defining lectin selectivity.•Strategies are presented for identifying reproducible glycan–lectin interactions.
Human innate immune lectins that recognize microbial glycans can conduct microbial surveillance and thereby help prevent infection. Structural analysis of soluble lectins has provided invaluable insight into how these proteins recognize their cognate carbohydrate ligands and how this recognition gives rise to biological function. In this opinion, we cover the structural features of lectins that allow them to mediate microbial recognition, highlighting examples from the collectin, Reg protein, galectin, pentraxin, ficolin and intelectin families. These analyses reveal how some lectins (e.g., human intelectin-1) can recognize glycan epitopes that are remarkably diverse, yet still differentiate between mammalian and microbial glycans. We additionally discuss strategies to identify lectins that recognize microbial glycans and highlight tools that facilitate these discovery efforts.
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