Protein Flexibility and Conformational Entropy in Ligand Design Targeting the Carbohydrate Recognition Domain of Galectin-3.
Diehl, Carl LU ; Engström, Olof ; Delaine, Tamara LU ; Håkansson, Maria LU ; Genheden, Samuel LU ; Modig, Kristofer LU
; Leffler, Hakon
LU
; Ryde, Ulf
LU
; Nilsson, Ulf
LU
and Akke, Mikael
LU
(2010)
In Journal of the American Chemical Society
132.
p.14577-14589
- Abstract
- Rational drug design is predicated on knowledge of the three-dimensional structure of the protein-ligand complex and the thermodynamics of ligand binding. Despite the fundamental importance of both enthalpy and entropy in driving ligand binding, the role of conformational entropy is rarely addressed in drug design. In this work, we have probed the conformational entropy and its relative contribution to the free energy of ligand binding to the carbohydrate recognition domain of galectin-3. Using a combination of NMR spectroscopy, isothermal titration calorimetry, and X-ray crystallography, we characterized the binding of three ligands with dissociation constants ranging over 2 orders of magnitude. (15)N and (2)H spin relaxation measurements... (More)
- Rational drug design is predicated on knowledge of the three-dimensional structure of the protein-ligand complex and the thermodynamics of ligand binding. Despite the fundamental importance of both enthalpy and entropy in driving ligand binding, the role of conformational entropy is rarely addressed in drug design. In this work, we have probed the conformational entropy and its relative contribution to the free energy of ligand binding to the carbohydrate recognition domain of galectin-3. Using a combination of NMR spectroscopy, isothermal titration calorimetry, and X-ray crystallography, we characterized the binding of three ligands with dissociation constants ranging over 2 orders of magnitude. (15)N and (2)H spin relaxation measurements showed that the protein backbone and side chains respond to ligand binding by increased conformational fluctuations, on average, that differ among the three ligand-bound states. Variability in the response to ligand binding is prominent in the hydrophobic core, where a distal cluster of methyl groups becomes more rigid, whereas methyl groups closer to the binding site become more flexible. The results reveal an intricate interplay between structure and conformational fluctuations in the different complexes that fine-tunes the affinity. The estimated change in conformational entropy is comparable in magnitude to the binding enthalpy, demonstrating that it contributes favorably and significantly to ligand binding. We speculate that the relatively weak inherent protein-carbohydrate interactions and limited hydrophobic effect associated with oligosaccharide binding might have exerted evolutionary pressure on carbohydrate-binding proteins to increase the affinity by means of conformational entropy. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1687773
- author
- Diehl, Carl
LU
; Engström, Olof
; Delaine, Tamara
LU
; Håkansson, Maria
LU
; Genheden, Samuel
LU
; Modig, Kristofer
LU
; Leffler, Hakon
LU
; Ryde, Ulf
LU
; Nilsson, Ulf
LU
and Akke, Mikael
LU
- organization
- publishing date
- 2010
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of the American Chemical Society
- volume
- 132
- pages
- 14577 - 14589
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- wos:000283276800053
- pmid:20873837
- scopus:77958035712
- pmid:20873837
- ISSN
- 1520-5126
- DOI
- 10.1021/ja105852y
- 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), Biophysical Chemistry (LTH) (011001011), Organic chemistry (S/LTH) (011001240), Theoretical Chemistry (S) (011001039), Department of Chemistry (011001220)
- id
- 36d74475-c30b-48e6-9709-f8d4bbf68c6a (old id 1687773)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/20873837?dopt=Abstract
- date added to LUP
- 2016-04-01 14:41:31
- date last changed
- 2023-03-28 05:31:00
@article{36d74475-c30b-48e6-9709-f8d4bbf68c6a,
abstract = {{Rational drug design is predicated on knowledge of the three-dimensional structure of the protein-ligand complex and the thermodynamics of ligand binding. Despite the fundamental importance of both enthalpy and entropy in driving ligand binding, the role of conformational entropy is rarely addressed in drug design. In this work, we have probed the conformational entropy and its relative contribution to the free energy of ligand binding to the carbohydrate recognition domain of galectin-3. Using a combination of NMR spectroscopy, isothermal titration calorimetry, and X-ray crystallography, we characterized the binding of three ligands with dissociation constants ranging over 2 orders of magnitude. (15)N and (2)H spin relaxation measurements showed that the protein backbone and side chains respond to ligand binding by increased conformational fluctuations, on average, that differ among the three ligand-bound states. Variability in the response to ligand binding is prominent in the hydrophobic core, where a distal cluster of methyl groups becomes more rigid, whereas methyl groups closer to the binding site become more flexible. The results reveal an intricate interplay between structure and conformational fluctuations in the different complexes that fine-tunes the affinity. The estimated change in conformational entropy is comparable in magnitude to the binding enthalpy, demonstrating that it contributes favorably and significantly to ligand binding. We speculate that the relatively weak inherent protein-carbohydrate interactions and limited hydrophobic effect associated with oligosaccharide binding might have exerted evolutionary pressure on carbohydrate-binding proteins to increase the affinity by means of conformational entropy.}},
author = {{Diehl, Carl and Engström, Olof and Delaine, Tamara and Håkansson, Maria and Genheden, Samuel and Modig, Kristofer and Leffler, Hakon and Ryde, Ulf and Nilsson, Ulf and Akke, Mikael}},
issn = {{1520-5126}},
language = {{eng}},
pages = {{14577--14589}},
publisher = {{The American Chemical Society (ACS)}},
series = {{Journal of the American Chemical Society}},
title = {{Protein Flexibility and Conformational Entropy in Ligand Design Targeting the Carbohydrate Recognition Domain of Galectin-3.}},
url = {{http://dx.doi.org/10.1021/ja105852y}},
doi = {{10.1021/ja105852y}},
volume = {{132}},
year = {{2010}},
}