Genetically Encoded Fragment-Based Discovery of Glycopeptide Ligands for Carbohydrate-Binding Proteins
Abstract
Here we describe an approach to accelerate the search for competitive inhibitors for carbohydrate-recognition domains (CRDs). Genetically encoded fragment-based-discovery (GE-FBD) uses selection of phagedisplayed glycopeptides to dock a glycan fragment at the CRD and guide selection of Synergistic peptide motifs adjacent to the CRD. Starting from concanavalin A (ConA), a mannose (Man)-binding protein, as a bait, we narrowed a library of 10 8 glycopeptides to 86 leads that share a consensus motif, Man-WYD. Validation of synthetic leads yielded Man-WYDLF that exhibited 40 50-fold enhancement in affinity over methyl α-D-mannopyranoside (MeMan). Lectin array Suggested specificity: Man-WYD derivative bound only to 3 out of 17 proteins-ConA, LcH, and PSA-that bind to Man. An X-ray structure of ConA.:Man-WYD proved that the trimannoside core and Man-WYD exhibit identical CRD docking; but their extra-CRD binding modes are significantly. different. Still, they have comparable affinity and selectivity for various Man-binding proteins. The intriguing observation provides new insight into functional mimicry :of carbohydrates by peptide ligands. GE-FBD may provide an alternative to rapidly search for competitive inhibitors for lectins.
- Authors:
-
- Univ. of Alberta, Edmonton, AB (Canada)
- Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Biology and Soft Matter Division
- New York Univ. (NYU), NY (United States). Biomedical Chemistry Inst.
- Univ. of Georgia, Athens, GA (United States)
- New England Biolabs, Ipswich, MA (United States)
- Univ. of Calgary, AB (Canada)
- National Univ. of Ireland, Galway (Ireland)
- Publication Date:
- Research Org.:
- Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Biological and Environmental Research (BER); Canada Foundation for Innovation (CFI); National Institutes of Health (NIH)
- OSTI Identifier:
- 1261431
- Grant/Contract Number:
- AC05-00OR22725; AC02- 06CH11357; R01 GM094919; P41 GM103390; 08/IN.1/B2070
- Resource Type:
- Journal Article: Accepted Manuscript
- Journal Name:
- Journal of the American Chemical Society
- Additional Journal Information:
- Journal Volume: 137; Journal Issue: 16; Journal ID: ISSN 0002-7863
- Publisher:
- American Chemical Society (ACS)
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Ng, Simon, Lin, Edith, Kitov, Pavel I., Tjhung, Katrina F., Gerlits, Oksana O., Deng, Lu, Kasper, Brian, Sood, Amika, Paschal, Beth M., Zhang, Ping, Ling, Chang-Chun, Klassen, John S., Noren, Christopher J., Mahal, Lara K., Woods, Robert J., Coates, Leighton, and Derda, Ratmir. Genetically Encoded Fragment-Based Discovery of Glycopeptide Ligands for Carbohydrate-Binding Proteins. United States: N. p., 2015.
Web. doi:10.1021/ja511237n.
Ng, Simon, Lin, Edith, Kitov, Pavel I., Tjhung, Katrina F., Gerlits, Oksana O., Deng, Lu, Kasper, Brian, Sood, Amika, Paschal, Beth M., Zhang, Ping, Ling, Chang-Chun, Klassen, John S., Noren, Christopher J., Mahal, Lara K., Woods, Robert J., Coates, Leighton, & Derda, Ratmir. Genetically Encoded Fragment-Based Discovery of Glycopeptide Ligands for Carbohydrate-Binding Proteins. United States. https://doi.org/10.1021/ja511237n
Ng, Simon, Lin, Edith, Kitov, Pavel I., Tjhung, Katrina F., Gerlits, Oksana O., Deng, Lu, Kasper, Brian, Sood, Amika, Paschal, Beth M., Zhang, Ping, Ling, Chang-Chun, Klassen, John S., Noren, Christopher J., Mahal, Lara K., Woods, Robert J., Coates, Leighton, and Derda, Ratmir. Fri .
"Genetically Encoded Fragment-Based Discovery of Glycopeptide Ligands for Carbohydrate-Binding Proteins". United States. https://doi.org/10.1021/ja511237n. https://www.osti.gov/servlets/purl/1261431.
@article{osti_1261431,
title = {Genetically Encoded Fragment-Based Discovery of Glycopeptide Ligands for Carbohydrate-Binding Proteins},
author = {Ng, Simon and Lin, Edith and Kitov, Pavel I. and Tjhung, Katrina F. and Gerlits, Oksana O. and Deng, Lu and Kasper, Brian and Sood, Amika and Paschal, Beth M. and Zhang, Ping and Ling, Chang-Chun and Klassen, John S. and Noren, Christopher J. and Mahal, Lara K. and Woods, Robert J. and Coates, Leighton and Derda, Ratmir},
abstractNote = {Here we describe an approach to accelerate the search for competitive inhibitors for carbohydrate-recognition domains (CRDs). Genetically encoded fragment-based-discovery (GE-FBD) uses selection of phagedisplayed glycopeptides to dock a glycan fragment at the CRD and guide selection of Synergistic peptide motifs adjacent to the CRD. Starting from concanavalin A (ConA), a mannose (Man)-binding protein, as a bait, we narrowed a library of 108 glycopeptides to 86 leads that share a consensus motif, Man-WYD. Validation of synthetic leads yielded Man-WYDLF that exhibited 40 50-fold enhancement in affinity over methyl α-D-mannopyranoside (MeMan). Lectin array Suggested specificity: Man-WYD derivative bound only to 3 out of 17 proteins-ConA, LcH, and PSA-that bind to Man. An X-ray structure of ConA.:Man-WYD proved that the trimannoside core and Man-WYD exhibit identical CRD docking; but their extra-CRD binding modes are significantly. different. Still, they have comparable affinity and selectivity for various Man-binding proteins. The intriguing observation provides new insight into functional mimicry :of carbohydrates by peptide ligands. GE-FBD may provide an alternative to rapidly search for competitive inhibitors for lectins.},
doi = {10.1021/ja511237n},
url = {https://www.osti.gov/biblio/1261431},
journal = {Journal of the American Chemical Society},
issn = {0002-7863},
number = 16,
volume = 137,
place = {United States},
year = {2015},
month = {4}
}
Web of Science
Works referencing / citing this record:
High‐Throughput Approaches in Carbohydrate‐Active Enzymology: Glycosidase and Glycosyl Transferase Inhibitors, Evolution, and Discovery
journal, July 2019
- Chao, Lemeng; Jongkees, Seino
- Angewandte Chemie, Vol. 131, Issue 37
Compositional Bias in Naïve and Chemically-modified Phage-Displayed Libraries uncovered by Paired-end Deep Sequencing
journal, January 2018
- He, Bifang; Tjhung, Katrina F.; Bennett, Nicholas J.
- Scientific Reports, Vol. 8, Issue 1