6OKD

Crystal Structure of human transferrin receptor in complex with a cystine-dense peptide

Summary for 6OKD

• Entry DOI: 10.2210/pdb6okd/pdb
• Descriptor: Transferrin receptor protein 1, transferrin receptor binding cystine-dense peptide, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (6 entities in total)
• Functional Keywords: protein-protein complex, cystine-dense peptide, transport protein-signaling protein complex, transport protein/signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 164220.86

Authors

Finton, K.A.K.,Rupert, P.B.,Strong, R.K. (deposition date: 2019-04-12, release date: 2020-04-15, Last modification date: 2024-10-30)

Primary citation

Crook, Z.R.,Girard, E.,Sevilla, G.P.,Merrill, M.,Friend, D.,Rupert, P.B.,Pakiam, F.,Nguyen, E.,Yin, C.,Ruff, R.O.,Hopping, G.,Strand, A.D.,Finton, K.A.K.,Coxon, M.,Mhyre, A.J.,Strong, R.K.,Olson, J.M.
A TfR-Binding Cystine-Dense Peptide Promotes Blood-Brain Barrier Penetration of Bioactive Molecules.
J.Mol.Biol., 432:3989-4009, 2020

PubMed Abstract: The 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. Cystine-dense peptides (CDPs) have drawn recent interest as drugs or drug-delivery vehicles. 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 (K 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.

PubMed: 32304700
DOI: 10.1016/j.jmb.2020.04.002

Experimental method

X-RAY DIFFRACTION (1.85 Å)