Mapping the energy landscape of protein-ligand binding via linear free energy relationships determined by protein NMR relaxation dispersion
Stenström, Olof LU ; Diehl, Carl LU ; Modig, Kristofer LU
; Nilsson, Ulf J.
LU
and Akke, Mikael
LU
(2021)
In RSC Chemical Biology
2(1).
p.259-265
- Abstract
Biochemical signaling is mediated by complexes between macromolecular receptors and their ligands, with the duration of the signal being directly related to the lifetime of the ligand-receptor complex. In the field of drug design, the recognition that drug efficacy in vivo depends on the lifetime of the drug-protein complex has spawned the concept of designing drugs with particular binding kinetics. To advance this field it is critical to investigate how the molecular details of designed ligands might affect the binding kinetics, as well as the equilibrium binding constant. Here we use protein NMR relaxation dispersion to determine linear free energy relationships involving the on- and off-rates and the affinity for a series of... (More)
Biochemical signaling is mediated by complexes between macromolecular receptors and their ligands, with the duration of the signal being directly related to the lifetime of the ligand-receptor complex. In the field of drug design, the recognition that drug efficacy in vivo depends on the lifetime of the drug-protein complex has spawned the concept of designing drugs with particular binding kinetics. To advance this field it is critical to investigate how the molecular details of designed ligands might affect the binding kinetics, as well as the equilibrium binding constant. Here we use protein NMR relaxation dispersion to determine linear free energy relationships involving the on- and off-rates and the affinity for a series of congeneric ligands targeting the carbohydrate recognition domain of galectin-3. Using this approach we determine the energy landscape and the position of the transition state along the reaction coordinate of protein-ligand binding. The results show that ligands exhibiting reduced off-rates achieve this by primarily stabilizing the bound state, but do not affect the transition state to any greater extent. The transition state forms early, that is, it is located significantly closer to the free state than to the bound state, suggesting a critical role of desolvation. Furthermore, the data suggest that different subclasses of ligands show different behavior with respect to these characteristics.
(Less)
- author
- Stenström, Olof
LU
; Diehl, Carl
LU
; Modig, Kristofer
LU
; Nilsson, Ulf J.
LU
and Akke, Mikael
LU
- organization
- publishing date
- 2021
- type
- Contribution to journal
- publication status
- published
- subject
- in
- RSC Chemical Biology
- volume
- 2
- issue
- 1
- pages
- 7 pages
- publisher
- Royal Society of Chemistry
- external identifiers
-
- pmid:34458786
- scopus:85116043334
- ISSN
- 2633-0679
- DOI
- 10.1039/d0cb00229a
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © The Royal Society of Chemistry.
- id
- 635b5a4d-1e02-492c-9ffb-ed879545b8c2
- date added to LUP
- 2021-10-14 16:52:40
- date last changed
- 2024-04-20 13:14:21
@article{635b5a4d-1e02-492c-9ffb-ed879545b8c2,
abstract = {{<p>Biochemical signaling is mediated by complexes between macromolecular receptors and their ligands, with the duration of the signal being directly related to the lifetime of the ligand-receptor complex. In the field of drug design, the recognition that drug efficacy <i>in vivo</i> depends on the lifetime of the drug-protein complex has spawned the concept of designing drugs with particular binding kinetics. To advance this field it is critical to investigate how the molecular details of designed ligands might affect the binding kinetics, as well as the equilibrium binding constant. Here we use protein NMR relaxation dispersion to determine linear free energy relationships involving the on- and off-rates and the affinity for a series of congeneric ligands targeting the carbohydrate recognition domain of galectin-3. Using this approach we determine the energy landscape and the position of the transition state along the reaction coordinate of protein-ligand binding. The results show that ligands exhibiting reduced off-rates achieve this by primarily stabilizing the bound state, but do not affect the transition state to any greater extent. The transition state forms early, that is, it is located significantly closer to the free state than to the bound state, suggesting a critical role of desolvation. Furthermore, the data suggest that different subclasses of ligands show different behavior with respect to these characteristics.</p>}},
author = {{Stenström, Olof and Diehl, Carl and Modig, Kristofer and Nilsson, Ulf J. and Akke, Mikael}},
issn = {{2633-0679}},
language = {{eng}},
number = {{1}},
pages = {{259--265}},
publisher = {{Royal Society of Chemistry}},
series = {{RSC Chemical Biology}},
title = {{Mapping the energy landscape of protein-ligand binding <i>via </i>linear free energy relationships determined by protein NMR relaxation dispersion}},
url = {{http://dx.doi.org/10.1039/d0cb00229a}},
doi = {{10.1039/d0cb00229a}},
volume = {{2}},
year = {{2021}},
}