Structural and Thermodynamic Studies on Cation- Interactions in Lectin-Ligand Complexes: High-Affinity Galectin-3 Inhibitors through Fine-Tuning of an Arginine-Arene Interaction
(2005) In Journal of the American Chemical Society 127(6). p.1737-1743- Abstract
- The high-resolution X-ray crystal structures of the carbohydrate recognition domain of human galectin-3 were solved in complex with N-acetyllactosamine (LacNAc) and the high-affinity inhibitor, methyl 2-acetamido-2-deoxy-4-O-(3-deoxy-3-[4-methoxy-2,3,5,6-tetrafluorobenzamido]--D-galactopyranose)--D-glucopyranoside, to gain insight into the basis for the affinity-enhancing effect of the 4-methoxy-2,3,5,6-tetrafluorobenzamido moiety. The structures show that the side chain of Arg144 stacks against the aromatic moiety of the inhibitor, an interaction made possible by a reorientation of the side chain relative to that seen in the LacNAc complex. Based on these structures, synthesis of second generation LacNAc derivatives carrying aromatic... (More)
- The high-resolution X-ray crystal structures of the carbohydrate recognition domain of human galectin-3 were solved in complex with N-acetyllactosamine (LacNAc) and the high-affinity inhibitor, methyl 2-acetamido-2-deoxy-4-O-(3-deoxy-3-[4-methoxy-2,3,5,6-tetrafluorobenzamido]--D-galactopyranose)--D-glucopyranoside, to gain insight into the basis for the affinity-enhancing effect of the 4-methoxy-2,3,5,6-tetrafluorobenzamido moiety. The structures show that the side chain of Arg144 stacks against the aromatic moiety of the inhibitor, an interaction made possible by a reorientation of the side chain relative to that seen in the LacNAc complex. Based on these structures, synthesis of second generation LacNAc derivatives carrying aromatic amides at 3'-C, followed by screening with a novel fluorescence polarization assay, has led to the identification of inhibitors with further enhanced affinity for galectin-3 (Kd 320 nM). The thermodynamic parameters describing the binding of the galectin-3 C-terminal to selected inhibitors were determined by isothermal titration calorimetry and showed that the affinity enhancements were due to favorable enthalpic contributions. These enhancements could be rationalized by the combined effects of the inhibitor aromatic structure on a cation- interaction and of direct interactions between the aromatic substituents and the protein. The results demonstrate that protein-ligand interactions can be significantly enhanced by the fine-tuning of arginine-arene interactions. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/158716
- author
- Sörme, Pernilla LU ; Arnoux, P ; Kahl-Knutsson, B ; Leffler, Hakon LU ; Rini, J and Nilsson, Ulf LU
- organization
- publishing date
- 2005
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of the American Chemical Society
- volume
- 127
- issue
- 6
- pages
- 1737 - 1743
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- pmid:15701008
- wos:000226951800044
- scopus:13644272606
- pmid:15701008
- ISSN
- 1520-5126
- DOI
- 10.1021/ja043475p
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Division of Microbiology, Immunology and Glycobiology - MIG (013025200), Organic chemistry (S/LTH) (011001240)
- id
- 4bfefe3b-c7bf-4c38-80f4-aea4dbb76509 (old id 158716)
- date added to LUP
- 2016-04-01 16:49:39
- date last changed
- 2022-04-15 07:21:28
@article{4bfefe3b-c7bf-4c38-80f4-aea4dbb76509, abstract = {{The high-resolution X-ray crystal structures of the carbohydrate recognition domain of human galectin-3 were solved in complex with N-acetyllactosamine (LacNAc) and the high-affinity inhibitor, methyl 2-acetamido-2-deoxy-4-O-(3-deoxy-3-[4-methoxy-2,3,5,6-tetrafluorobenzamido]--D-galactopyranose)--D-glucopyranoside, to gain insight into the basis for the affinity-enhancing effect of the 4-methoxy-2,3,5,6-tetrafluorobenzamido moiety. The structures show that the side chain of Arg144 stacks against the aromatic moiety of the inhibitor, an interaction made possible by a reorientation of the side chain relative to that seen in the LacNAc complex. Based on these structures, synthesis of second generation LacNAc derivatives carrying aromatic amides at 3'-C, followed by screening with a novel fluorescence polarization assay, has led to the identification of inhibitors with further enhanced affinity for galectin-3 (Kd 320 nM). The thermodynamic parameters describing the binding of the galectin-3 C-terminal to selected inhibitors were determined by isothermal titration calorimetry and showed that the affinity enhancements were due to favorable enthalpic contributions. These enhancements could be rationalized by the combined effects of the inhibitor aromatic structure on a cation- interaction and of direct interactions between the aromatic substituents and the protein. The results demonstrate that protein-ligand interactions can be significantly enhanced by the fine-tuning of arginine-arene interactions.}}, author = {{Sörme, Pernilla and Arnoux, P and Kahl-Knutsson, B and Leffler, Hakon and Rini, J and Nilsson, Ulf}}, issn = {{1520-5126}}, language = {{eng}}, number = {{6}}, pages = {{1737--1743}}, publisher = {{The American Chemical Society (ACS)}}, series = {{Journal of the American Chemical Society}}, title = {{Structural and Thermodynamic Studies on Cation- Interactions in Lectin-Ligand Complexes: High-Affinity Galectin-3 Inhibitors through Fine-Tuning of an Arginine-Arene Interaction}}, url = {{http://dx.doi.org/10.1021/ja043475p}}, doi = {{10.1021/ja043475p}}, volume = {{127}}, year = {{2005}}, }