Complex of human Melanotransferrin and SC57.32 Fab fragment reveals novel interdomain arrangement with ferric N-lobe and open C-lobe.
Acetylglucosamine
Animals
Biological Transport
Blood-Brain Barrier
/ metabolism
Drug Delivery Systems
Drug Design
Gene Expression
Humans
Immunoglobulin Fab Fragments
/ chemistry
Iron
/ metabolism
Macaca fascicularis
Melanoma
/ etiology
Membrane Glycoproteins
/ chemistry
Mice
Protein Binding
Protein Domains
Triple Negative Breast Neoplasms
/ genetics
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
12 01 2021
12 01 2021
Historique:
received:
17
07
2020
accepted:
01
12
2020
entrez:
13
1
2021
pubmed:
14
1
2021
medline:
28
8
2021
Statut:
epublish
Résumé
Melanotransferrin (MTf) is an iron-binding member of the transferrin superfamily that can be membrane-anchored or secreted in serum. On cells, it can mediate transferrin-independent iron uptake and promote proliferation. In serum, it is a transcytotic iron transporter across the blood-brain barrier. MTf has been exploited as a drug delivery carrier to the brain and as an antibody-drug conjugate (ADC) target due to its oncogenic role in melanoma and its elevated expression in triple-negative breast cancer (TNBC). For treatment of TNBC, an MTf-targeting ADC completed a phase I clinical trial (NCT03316794). The structure of its murine, unconjugated Fab fragment (SC57.32) is revealed here in complex with MTf. The MTf N-lobe is in an active and iron-bound, closed conformation while the C-lobe is in an open conformation incompatible with iron binding. This combination of active and inactive domains displays a novel inter-domain arrangement in which the C2 subdomain angles away from the N-lobe. The C2 subdomain also contains the SC57.32 glyco-epitope, which comprises ten protein residues and two N-acetylglucosamines. Our report reveals novel features of MTf and provides a point of reference for MTf-targeting, structure-guided drug design.
Identifiants
pubmed: 33436675
doi: 10.1038/s41598-020-79090-8
pii: 10.1038/s41598-020-79090-8
pmc: PMC7804310
doi:
Substances chimiques
Immunoglobulin Fab Fragments
0
MELTF protein, human
0
Membrane Glycoproteins
0
Iron
E1UOL152H7
Acetylglucosamine
V956696549
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
566Références
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