Molecular dynamics simulations elucidate oligosaccharide recognition pathways by galectin-3 at atomic resolution.
MD simulation
Markov state model
drug residence time
galectin
ligand binding
oligosaccharide
recognition
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
received:
08
07
2021
revised:
29
09
2021
accepted:
29
09
2021
pubmed:
8
10
2021
medline:
15
12
2021
entrez:
7
10
2021
Statut:
ppublish
Résumé
The recognition of carbohydrates by lectins plays key roles in diverse cellular processes such as cellular adhesion, proliferation, and apoptosis, which makes it a therapeutic target of significance against cancers. One of the most functionally active lectins, galectin-3 is distinctively known for its specific binding affinity toward β-galactoside. However, despite the prevalence of high-resolution crystallographic structures, the mechanistic basis and more significantly, the dynamic process underlying carbohydrate recognition by galectin-3 are currently elusive. To this end, we employed extensive Molecular Dynamics simulations to unravel the complete binding event of human galectin-3 with its native natural ligand N-acetyllactosamine (LacNAc) at atomic precision. The simulation trajectory demonstrates that the oligosaccharide diffuses around the protein and eventually identifies and binds to the biologically designated binding site of galectin-3 in real time. The simulated bound pose correlates with the crystallographic pose with atomic-level accuracy and recapitulates the signature stabilizing galectin-3/oligosaccharide interactions. The recognition pathway also reveals a set of transient non-native ligand poses in its course to the receptor. Interestingly, kinetic analysis in combination with a residue-level picture revealed that the key to the efficacy of a more active structural variant of the LacNAc lay in the ligand's resilience against disassociation from galectin-3. By catching the ligand in the act of finding its target, our investigations elucidate the detailed recognition mechanism of the carbohydrate-binding domain of galectin-3 and underscore the importance of ligand-target binary complex residence time in understanding the structure-activity relationship of cognate ligands.
Identifiants
pubmed: 34619151
pii: S0021-9258(21)01074-7
doi: 10.1016/j.jbc.2021.101271
pmc: PMC8571523
pii:
doi:
Substances chimiques
Amino Sugars
0
Blood Proteins
0
Galectins
0
LGALS3 protein, human
0
Oligosaccharides
0
N-acetyllactosamine
3Y5B2K5OOK
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
101271Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
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