Titre :

Discovery of a novel lactate dehydrogenase tetramerization domain using epitope mapping and peptides

Auteur(s) :

Thabault, L. [Auteur]
Université Catholique de Louvain = Catholic University of Louvain [UCL]
Liberelle, Maxime [Auteur]
Université Catholique de Louvain = Catholic University of Louvain [UCL]
Koruza, K. [Auteur]
Vrije Universiteit Brussel [Bruxelles] [VUB]
Yildiz, E. [Auteur]
Université Catholique de Louvain = Catholic University of Louvain [UCL]
Joudiou, N. [Auteur]
Université Catholique de Louvain = Catholic University of Louvain [UCL]
Messens, J. [Auteur]
Vrije Universiteit Brussel [Bruxelles] [VUB]
Brisson, L. [Auteur]
Niche, Nutrition, Cancer et métabolisme oxydatif [N2Cox]
Wouters, J. [Auteur]
Université de Namur [Namur] [UNamur]
Sonveaux, P. [Auteur]
Université Catholique de Louvain = Catholic University of Louvain [UCL]
Frederick, R. [Auteur]
Université Catholique de Louvain = Catholic University of Louvain [UCL]

Titre de la revue :

J. Biol. Chem.

Nom court de la revue :

J Biol Chem

Numéro :

296

Pagination :

100422

Éditeur :

American Society for Biochemistry and Molecular Biology

Date de publication :

2023-05-30

ISSN :

1083-351X

Discipline(s) HAL :

Sciences du Vivant [q-bio]

Résumé en anglais : [en]

Despite being initially regarded as a metabolic waste product, lactate is now considered to serve as a primary fuel for the tricarboxylic acid cycle in cancer cells. At the core of lactate metabolism, lactate dehydrogenases ...
Lire la suite >Despite being initially regarded as a metabolic waste product, lactate is now considered to serve as a primary fuel for the tricarboxylic acid cycle in cancer cells. At the core of lactate metabolism, lactate dehydrogenases (LDHs) catalyze the interconversion of lactate to pyruvate and as such represent promising targets in cancer therapy. However, direct inhibition of the LDH active site is challenging from physicochemical and selectivity standpoints. However, LDHs are obligate tetramers. Thus, targeting the LDH tetrameric interface has emerged as an appealing strategy. In this work, we examine a dimeric construct of truncated human LDH to search for new druggable sites. We report the identification and characterization of a new cluster of interactions in the LDH tetrameric interface. Using nanoscale differential scanning fluorimetry, chemical denaturation, and mass photometry, we identified several residues (E62, D65, L71, and F72) essential for LDH tetrameric stability. Moreover, we report a family of peptide ligands based on this cluster of interactions. We next demonstrated these ligands to destabilize tetrameric LDHs through binding to this new tetrameric interface using nanoscale differential scanning fluorimetry, NMR water–ligand observed via gradient spectroscopy, and microscale thermophoresis. Altogether, this work provides new insights on the LDH tetrameric interface as well as valuable pharmacological tools for the development of LDH tetramer disruptors.Lire moins >

Langue :

Anglais

Audience :

Internationale

Vulgarisation :

Non

Établissement(s) :

Université de Lille
Inserm
CHU Lille

Collections :

• Lille Neurosciences & Cognition (LilNCog) - U 1172

Date de dépôt :

2024-01-16T02:16:50Z
2024-10-23T10:30:52Z