Crystal structures of HER3 extracellular domain 4 in complex with the designed ankyrin-repeat protein D5.
DARPins
EGFR family
HER3
protein engineering
tumor targeting
Journal
Acta crystallographica. Section F, Structural biology communications
ISSN: 2053-230X
Titre abrégé: Acta Crystallogr F Struct Biol Commun
Pays: United States
ID NLM: 101620319
Informations de publication
Date de publication:
01 Jul 2021
01 Jul 2021
Historique:
received:
06
04
2021
accepted:
09
06
2021
entrez:
1
7
2021
pubmed:
2
7
2021
medline:
15
12
2021
Statut:
ppublish
Résumé
The members of the human epidermal growth factor receptor (HER) family are among the most intensely studied oncological targets. HER3 (ErbB3), which had long been neglected, has emerged as a key oncogene, regulating the activity of other receptors and being involved in progression and tumor escape in multiple types of cancer. Designed ankyrin-repeat proteins (DARPins) serve as antibody mimetics that have proven to be useful in the clinic, in diagnostics and in research. DARPins have previously been selected against EGFR (HER1), HER2 and HER4. In particular, their combination into bivalent binders that separate or lock receptors in their inactive conformation has proved to be a promising strategy for the design of potent anticancer therapeutics. Here, the selection of DARPins targeting extracellular domain 4 of HER3 (HER3d4) is described. One of the selected DARPins, D5, in complex with HER3d4 crystallized in two closely related crystal forms that diffracted to 2.3 and 2.0 Å resolution, respectively. The DARPin D5 epitope comprises HER3d4 residues 568-577. These residues also contribute to interactions within the tethered (inactive) and extended (active) conformations of the extracellular domain of HER3.
Identifiants
pubmed: 34196609
pii: S2053230X21006002
doi: 10.1107/S2053230X21006002
pmc: PMC8248824
doi:
Substances chimiques
ERBB3 protein, human
EC 2.7.10.1
Receptor, ErbB-3
EC 2.7.10.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
192-201Subventions
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
ID : 310030_192689
Informations de copyright
open access.
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