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Genetically encoded fragment-based discovery of glycopeptide ligands for carbohydrate-binding proteins

Ng, Simon
; 
Lin, Edith
; 
Kitov, Pavel I.
; 
Tjhung, Katrina F.
; 
Gerlits, Oksana O.
; 
Deng, Lu
; 
Kasper, Brian
; 
Sood, Amika
; 
Paschal, Beth M.
; 
Zhang, Ping
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Repository DOI
Publication Date
2015-04-29
Keywords
dc-sign, structural basis, concanavalin-a, library, phage, lectin, inhibitors, peptides, mimicry, glycobiology
Type
Article
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Citation
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 (2015). Genetically encoded fragment-based discovery of glycopeptide ligands for carbohydrate-binding proteins. Journal of the American Chemical Society 137 (16), 5248-5251
Abstract
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 alpha-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.
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Publisher
American Chemical Society (ACS)
Publisher DOI
10.1021/ja511237n
Rights
Attribution-NonCommercial-NoDerivs 3.0 Ireland
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Externally hosted open access publications with University of Galway authors (2)