Unmasking ligand conformational entropy in the recognition of blood group antigens

Session: 
S3.2 Spectroscopy tools to study carbohydrate interactions
Code: 
OL3.2.2
Location (hall): 
Mannose
Start/end time: 
Monday, July 1, 2019 - 17:30 to 17:45
Ana
Gimeno

Ana Gimeno1, Pablo  Valverde1, Sara Bertuzzi1, Sandra Delgado1, Manuel Álvaro Berbís2, J.  Echavarren2, Alessandra Lacetera2, Sonsoles Martín-Santamaría2, Avadhesha Surolia3, Francisco Javier Cañada2, Jesús Jiménez-Barbero1,4,5, Ana  Ardá1

1Cic Biogune, Derio, Spain, 2CIB-CSIC , Madrid, Spain, 3Indian Institute of Science, Bangalore, India, 4Ikerbasque, Basque Foundation for Science, Bilbao, Spain, 5II Faculty of Science and Technology University of the Basque Country, EHU-UPV , Leioa, Spain

Ligand conformational entropy is generally claimed as an important contribution in carbohydrate recognition events. Indeed, glycans are characterized by an intrinsic flexibility around the glycosidic linkages, and thus, except for isolated cases,[1] the loss of conformational entropy of the sugar upon complex formation strongly impacts the entropy of the binding process. However, this contribution is generally rather difficult to address. 

Herein, by employing a multidisciplinary approach combining structural, conformational, binding energy and kinetic information, we have disclosed the role of the conformational entropy in the recognition of the histo blood group antigens A and B by human galectin-3, a lectin of biomedical interest.[2] These rigid natural antigens are pre-organized ligands for hGal-3, being locked in the bioactive conformation. The restriction of the conformational flexibility rendered mostly by the branched Fucose residue,[3] modulates the thermodynamics and kinetics of the binding process, providing the impetus for the high affinity interaction. In fact, the conformational restriction observed for A- and B-BGA reduces the kinetic barrier of the association process and favorably impacts on the binding entropy. Thus, this study highlights the effect of glycan flexibility on the kinetics and thermodynamics of the binding process and provides inspiration for the design of high affinity ligands as antagonists for hGal-3 or other lectins of biomedical relevance.[4]

References: 
  1. a) Sager, C.P.; Fiege, B.; Zihlmann, P.; Vannam, R.; Rabbani, S.; Jakob, R. P.; Preston, R. C.; Zalewski, A.; Maier, T.; Peczuh, M. W.; Ernst, B. Chem Sci. 2017, 9, 646-654. b) Topin, J.; Lelimousin, M., Arnaud, J.; Audfray, A.; Pérez, S.; Varrot, A.; Imberty, A. ACS Chem. Biol. 2016, 11, 2011–2020. c) Binder, F. P. C.; Lemme, K.; Preston, R. C.; Ernst, B. Angew. Chem. Int. Ed. 2012, 51, 7327–7331, and references cited therein. 
  2. Girard, A.; Magnani, J. L. Trends Glycosci. Glyc. 2018, 30, SE211-SE220.
  3. a) Imberty, A.; Pérez, S. Chem. Rev. 2000, 100, 4567−4588. b) Zierke, M.; Smieško, M.; Rabbani, S.; Aeschbacher, T.; Cutting, B.; Allain, F. H.-T.; Schubert, M.; Ernst, B. J. Am. Chem. Soc., 2013, 135, 13464-13472. c) Aeschbacher, T.; Zierke, M.; Smiesko, M.; Collot, M.; Mallet, J-M.; Ernst, B.; Allain, F. H.-T.; Schubert; M. Chem. Eur. J. 2017, 23, 11598- 11610. 
  4. Gimeno, A.; Delgado, S.; Valverde, P.; Bertuzzi, S.; Berbís, M. A.; Echavarren, J.; Lacetera, A.; Martín-Santamaría, S.; Surolia, A.; Cañada, F. J.; Jiménez-Barbero, J.; Ardá, A.. Submitted. 

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