Diacritic Binding of an Indenoindole Inhibitor by CK2α Paralogs Explored by a Reliable Path to Atomic Resolution CK2α′ Structures - Université Claude Bernard Lyon 1 Accéder directement au contenu
Article Dans Une Revue ACS Omega Année : 2019

Diacritic Binding of an Indenoindole Inhibitor by CK2α Paralogs Explored by a Reliable Path to Atomic Resolution CK2α′ Structures

Résumé

CK2α and CK2α′ are the two isoforms of the catalytic subunit of human protein kinase CK2, an important target for cancer therapy. They have similar, albeit not identical functional and structural properties, and were occasionally reported to be inhibited with distinct efficacies by certain ATP-competitive ligands. Here, we present THN27, an indeno[1,2-b]indole derivative, as a further inhibitor with basal isoform selectivity. The selectivity disappears when measured using CK2α/CK2α′ complexes with CK2β, the regulatory CK2 subunit. Co-crystal structures of THN27 with CK2α and CK2α′ reveal that subtle differences in the conformational variability of the inter-domain hinge region are correlated with the observed effect. In the case of CK2α′, a crystallographically problematic protein so far, this comparative structural analysis required the development of an experimental strategy that finally enables atomic resolution structure determinations with ab initio phasing of potentially any ATP-competitive CK2 inhibitor and possibly many non-ATP-competitive ligands as well bound to CK2α′.
Fichier principal
Vignette du fichier
acsomega.8b03415-MLB.pdf (5.57 Mo) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)
Loading...

Dates et versions

hal-02077897 , version 1 (24-03-2019)

Identifiants

Citer

Dirk Lindenblatt, Anna Nickelsen, Violetta M Applegate, Jennifer Hochscherf, Benedict Witulski, et al.. Diacritic Binding of an Indenoindole Inhibitor by CK2α Paralogs Explored by a Reliable Path to Atomic Resolution CK2α′ Structures. ACS Omega, 2019, 4 (3), pp.5471-5478. ⟨10.1021/acsomega.8b03415⟩. ⟨hal-02077897⟩
70 Consultations
55 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More