6okd | pdb_00006okd
Crystal Structure of human transferrin receptor in complex with a cystine-dense peptide
Structural highlights
FunctionTFR1_HUMAN Cellular uptake of iron occurs via receptor-mediated endocytosis of ligand-occupied transferrin receptor into specialized endosomes. Endosomal acidification leads to iron release. The apotransferrin-receptor complex is then recycled to the cell surface with a return to neutral pH and the concomitant loss of affinity of apotransferrin for its receptor. Transferrin receptor is necessary for development of erythrocytes and the nervous system (By similarity). A second ligand, the heditary hemochromatosis protein HFE, competes for binding with transferrin for an overlapping C-terminal binding site.[1] Publication Abstract from PubMedThe impenetrability of the blood-brain barrier (BBB) to most conventional drugs impedes the treatment of central nervous system (CNS) disorders. Interventions for diseases like brain cancer, neurodegeneration, or age-associated inflammatory processes require varied approaches to CNS drug delivery. Of recent interest as drugs or drug-delivery vehicles are cystine-dense peptides (CDPs). Found throughout the phylogenetic tree, often in drug-like roles, their size, stability, and protein interaction capabilities make CDPs an attractive mid-size biologic scaffold to complement conventional antibody-based drugs. Here, we describe the identification, maturation, characterization, and utilization of a CDP that binds to the transferrin receptor (TfR), a native receptor and BBB transporter for the iron chaperone transferrin. We developed variants with varying binding affinities (KD as low as 216 pM), co-crystallized it with the receptor, and confirmed murine cross-reactivity. It accumulates in the mouse CNS at ~25% of blood levels (CNS blood content is only ~1-6%), and delivers neurotensin, an otherwise non-BBB-penetrant neuropeptide, at levels capable of modulating CREB signaling in the mouse brain. Our work highlights the utility of CDPs as a diverse, easy-to-screen scaffold family worthy of inclusion in modern drug discovery strategies, demonstrated by the discovery of a candidate CNS drug delivery vehicle ready for further optimization and preclinical development. A TfR-Binding Cystine-Dense Peptide Promotes Blood-Brain Barrier Penetration of Bioactive Molecules.,Crook ZR, Girard E, Sevilla GP, Merrill M, Friend D, Rupert PB, Pakiam F, Nguyen E, Yin C, Ruff RO, Hopping G, Strand AD, Finton KAK, Coxon M, Mhyre AJ, Strong RK, Olson JM J Mol Biol. 2020 Apr 15. pii: S0022-2836(20)30279-5. doi:, 10.1016/j.jmb.2020.04.002. PMID:32304700[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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