4CZS

Discovery of Glycomimetic Ligands via Genetically-encoded Library of Phage displaying Mannose-peptides

Summary for 4CZS

• Entry DOI: 10.2210/pdb4czs/pdb
• Descriptor: Concanavalin V, MAN-WYD, CALCIUM ION, ... (6 entities in total)
• Functional Keywords: sugar binding protein
• Biological source: Canavalia cathartica; More
• Total number of polymer chains: 8
• Total formula weight: 105920.65

Authors

Ng, S.,Lin, E.,Tjhung, K.F.,Gerlits, O.,Sood, A.,Kasper, B.,Deng, L.,Kitov, P.I.,Matochko, W.L.,Paschal, B.M.,Noren, C.J.,Klassen, J.,Mahal, L.K.,Coates, L.,Woods, R.J.,Derda, R. (deposition date: 2014-04-22, release date: 2015-04-22, Last modification date: 2022-12-07)

Primary citation

Ng, S.,Lin, E.,Kitov, P.I.,Tjhung, K.F.,Gerlits, O.O.,Deng, L.,Kasper, B.,Sood, A.,Paschal, B.M.,Zhang, P.,Ling, C.C.,Klassen, J.S.,Noren, C.J.,Mahal, L.K.,Woods, R.J.,Coates, L.,Derda, R.
Genetically-Encoded Fragment-Based Discovery of Glycopeptide Ligands for Carbohydrate-Binding Proteins.
J.Am.Chem.Soc., 137:5248-, 2015

PubMed 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 phage-displayed 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.

PubMed: 25860443
DOI: 10.1021/JA511237N

Experimental method

X-RAY DIFFRACTION (1.73 Å)