6OKE
Crystal structure of an apo Transferrin-Receptor-Binding cystine-dense peptide
Summary for 6OKE
| Entry DOI | 10.2210/pdb6oke/pdb |
| Related | 6OKD |
| Descriptor | Transferrin-Receptor Binding Peptide (2 entities in total) |
| Functional Keywords | alpha-helical hairpin, cystine-dense, signaling protein |
| Biological source | Monosiga brevicollis |
| Total number of polymer chains | 4 |
| Total formula weight | 23838.47 |
| Authors | Rupert, P.B.,Strong, R.K. (deposition date: 2019-04-12, release date: 2020-04-15, Last modification date: 2024-11-20) |
| 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 Cited by 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: 32304700DOI: 10.1016/j.jmb.2020.04.002 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.55 Å) |
Structure validation
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