Author
Moriz Mayer
Bio: Moriz Mayer is an academic researcher from University of Hamburg. The author has contributed to research in topics: Binding site & Ligand (biochemistry). The author has an hindex of 5, co-authored 5 publications receiving 2735 citations.
Papers
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TL;DR: Fast identification of binding activity directly from mixtures of potential ligands is possible with the NMR method described, which is based on saturation transfer to molecules in direct contact to a protein.
Abstract: Fast identification of binding activity directly from mixtures of potential ligands is possible with the NMR method described, which is based on saturation transfer to molecules in direct contact to a protein. In addition, the ligand's binding epitope is easily identified. High sensitivity and ease of use are the principal advantages of this method. The picture shows the normal 1D NMR spectrum of a mixture and the spectrum obtained by applying the STD method, which exclusively shows signals from molecules with binding affinity.
1,432 citations
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TL;DR: Analysis of STD NMR experiments performed under competitive conditions proved that the two saccharides studied bind at the same receptor site, thereby ruling out unspecific binding.
Abstract: A protocol based on saturation transfer difference (STD) NMR spectra was developed to characterize the binding interactions at an atom level, termed group epitope mapping (GEM). As an example we chose the well-studied system of galactose binding to the 120-kDa lectin Ricinus communis agglutinin I (RCA120). As ligands we used methyl β-d-galactoside and a biantennary decasaccharide. Analysis of the saturation transfer effects of methyl β-d-galactoside showed that the H2, H3, and H4 protons are saturated to the highest degree, giving evidence of their close proximity to protons of the RCA120 lectin. The direct interaction of the lectin with this region of the galactose is in excellent agreement with results obtained from the analysis of the binding specificities of many chemically modified galactose derivatives (Bhattacharyya, L.; Brewer, C. F. Eur. J. Biochem. 1988, 176, 207−212). This new NMR technique can identify the binding epitope of even complex ligands very quickly, which is a great improvement over ...
1,069 citations
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179 citations
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TL;DR: In this article, a schnelle bestimmung von Bindungsaktivitat direkt aus Mischungen potentieller Liganden is discussed.
Abstract: Eine schnelle Bestimmung von Bindungsaktivitat direkt aus Mischungen potentieller Liganden ist mit der hier beschriebenen NMR-Methode moglich, bei der der Sattigungstransfer auf kurzzeitig an ein Protein gebundene Molekule genutzt wird. Zusatzlich last sich das Bindungsepitop sehr einfach ermitteln. Hohe Empfindlichkeit und einfache Anwendung sind wesentliche Vorteile des Verfahrens. Das Bild zeigt das normale 1D-NMR-Spektrum einer Mischung und das mit der STD-Methode prozessierte Spektrum, das nur noch die Signale des bindenden Molekuls enthalt.
177 citations
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TL;DR: Of the five fa derivatives, it is found that fa-Phe, fa-Trp, and fa-Gly-Leu-NH(2) bind more strongly to ACE than the other two, and a rapid screening of binding specificity from mixtures is possible by using a large excess of ligand in transferred NOE studies, even when relatively small amounts of protein are present.
Abstract: The interaction of five furylacryloyl (fa)-amino acid derivatives, fa-Phe, fa-Phe-Phe, fa-Gly-Leu-NH2, fa-Ala-Lys, and fa-Trp, with angiotensin-converting enzyme (ACE), a protein of MW = 130 kDa, w...
64 citations
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TL;DR: Here, illustrative examples are used to discuss general strategies for addressing the challenges inherent in the discovery and characterization of small-molecule inhibitors of protein–protein interactions.
Abstract: Protein–protein interactions have a key role in most biological processes, and offer attractive opportunities for therapeutic intervention. Developing small molecules that modulate protein–protein interactions is difficult, owing to issues such as the lack of well-defined binding pockets. Nevertheless, there has been important progress in this endeavour in recent years. Here, we use illustrative examples to discuss general strategies for addressing the challenges inherent in the discovery and characterization of small-molecule inhibitors of protein–protein interactions.
1,575 citations
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TL;DR: Analysis of STD NMR experiments performed under competitive conditions proved that the two saccharides studied bind at the same receptor site, thereby ruling out unspecific binding.
Abstract: A protocol based on saturation transfer difference (STD) NMR spectra was developed to characterize the binding interactions at an atom level, termed group epitope mapping (GEM). As an example we chose the well-studied system of galactose binding to the 120-kDa lectin Ricinus communis agglutinin I (RCA120). As ligands we used methyl β-d-galactoside and a biantennary decasaccharide. Analysis of the saturation transfer effects of methyl β-d-galactoside showed that the H2, H3, and H4 protons are saturated to the highest degree, giving evidence of their close proximity to protons of the RCA120 lectin. The direct interaction of the lectin with this region of the galactose is in excellent agreement with results obtained from the analysis of the binding specificities of many chemically modified galactose derivatives (Bhattacharyya, L.; Brewer, C. F. Eur. J. Biochem. 1988, 176, 207−212). This new NMR technique can identify the binding epitope of even complex ligands very quickly, which is a great improvement over ...
1,069 citations
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TL;DR: The structure of V1/V2 in complex with PG9 is reported, identifying a paradigm of antibody recognition for highly glycosylated antigens, which—with PG9—involves a site of vulnerability comprising just two glycans and a strand.
Abstract: Variable regions 1 and 2 (V1/V2) of human immunodeficiency virus-1 (HIV-1) gp120 envelope glycoprotein are critical for viral evasion of antibody neutralization, and are themselves protected by extraordinary sequence diversity and N-linked glycosylation. Human antibodies such as PG9 nonetheless engage V1/V2 and neutralize 80% of HIV-1 isolates. Here we report the structure of V1/V2 in complex with PG9. V1/V2 forms a four-stranded β-sheet domain, in which sequence diversity and glycosylation are largely segregated to strand-connecting loops. PG9 recognition involves electrostatic, sequence-independent and glycan interactions: the latter account for over half the interactive surface but are of sufficiently weak affinity to avoid autoreactivity. The structures of V1/V2-directed antibodies CH04 and PGT145 indicate that they share a common mode of glycan penetration by extended anionic loops. In addition to structurally defining V1/V2, the results thus identify a paradigm of antibody recognition for highly glycosylated antigens, which-with PG9-involves a site of vulnerability comprising just two glycans and a strand.
832 citations
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TL;DR: Here, examples from 25 different protein targets are used to describe chemical strategies that exploit structural knowledge to rapidly develop fragments into high-affinity leads.
Abstract: Fragment-based lead discovery is gaining momentum in both large pharmaceutical companies and biotechnology laboratories as a complementary approach to traditional screening. This is because fragment-based approaches require significantly fewer compounds to be screened and synthesized, and are showing a high success rate in generating chemical series with lead-like properties. Compared with traditional screening hits, the starting fragments have considerably lower molecular mass, and although the binding interactions of these fragments with a target protein are weak, they are structurally understood through X-ray crystallography or NMR, and they exhibit high 'ligand efficiency'. Here, we use examples from 25 different protein targets to describe chemical strategies that exploit this structural knowledge to rapidly develop fragments into high-affinity leads.
743 citations
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TL;DR: Examples of approved carbohydrate-derived drugs are examined, the potential of carbohydrate-binding proteins as new drug targets are discussed (focusing on the lectin families) and ways to overcome the challenges of developing this unique class of novel therapeutics are considered.
Abstract: Carbohydrates are the most abundant natural products. Besides their role in metabolism and as structural building blocks, they are fundamental constituents of every cell surface, where they are involved in vital cellular recognition processes. Carbohydrates are a relatively untapped source of new drugs and therefore offer exciting new therapeutic opportunities. Advances in the functional understanding of carbohydrate-protein interactions have enabled the development of a new class of small-molecule drugs, known as glycomimetics. These compounds mimic the bioactive function of carbohydrates and address the drawbacks of carbohydrate leads, namely their low activity and insufficient drug-like properties. Here, we examine examples of approved carbohydrate-derived drugs, discuss the potential of carbohydrate-binding proteins as new drug targets (focusing on the lectin families) and consider ways to overcome the challenges of developing this unique class of novel therapeutics.
664 citations