6wrv
From Proteopedia
Crystal structure of computationally designed protein 3DS18 in complex with the human Transferrin receptor ectodomain
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 de novo design of polar protein-protein interactions is challenging because of the thermodynamic cost of stripping water away from the polar groups. Here, we describe a general approach for designing proteins which complement exposed polar backbone groups at the edge of beta sheets with geometrically matched beta strands. We used this approach to computationally design small proteins that bind to an exposed beta sheet on the human transferrin receptor (hTfR), which shuttles interacting proteins across the blood-brain barrier (BBB), opening up avenues for drug delivery into the brain. We describe a design which binds hTfR with a 20 nM K(d), is hyperstable, and crosses an in vitro microfluidic organ-on-a-chip model of the human BBB. Our design approach provides a general strategy for creating binders to protein targets with exposed surface beta edge strands. Transferrin receptor targeting by de novo sheet extension.,Sahtoe DD, Coscia A, Mustafaoglu N, Miller LM, Olal D, Vulovic I, Yu TY, Goreshnik I, Lin YR, Clark L, Busch F, Stewart L, Wysocki VH, Ingber DE, Abraham J, Baker D Proc Natl Acad Sci U S A. 2021 Apr 27;118(17):e2021569118. doi: , 10.1073/pnas.2021569118. PMID:33879614[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Homo sapiens | Large Structures | Synthetic construct | Abraham J | Baker D | Clark L | Coscia A | Olal D | Sahtoe DD