6WRX

Crystal structure of computationally designed protein 2DS25.1 in complex with the human Transferrin receptor ectodomain

Summary for 6WRX

• Entry DOI: 10.2210/pdb6wrx/pdb
• Descriptor: Transferrin receptor protein 1, Computationally designed protein 2DS25.1, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• Functional Keywords: complex, beta sheet, receptor, de novo protein, de novo protein-metal transport complex, de novo protein/metal transport
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 167017.81

Authors

Abraham, J.,Coscia, A.,Olal, D.,Sahtoe, D.D.,Baker, D.,Clark, L. (deposition date: 2020-04-30, release date: 2021-04-28, Last modification date: 2024-10-09)

Primary citation

Sahtoe, D.D.,Coscia, A.,Mustafaoglu, N.,Miller, L.M.,Olal, D.,Vulovic, I.,Yu, T.Y.,Goreshnik, I.,Lin, Y.R.,Clark, L.,Busch, F.,Stewart, L.,Wysocki, V.H.,Ingber, D.E.,Abraham, J.,Baker, D.
Transferrin receptor targeting by de novo sheet extension.
Proc.Natl.Acad.Sci.USA, 118:-, 2021

PubMed Abstract: The 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 , 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.

PubMed: 33879614
DOI: 10.1073/pnas.2021569118

Experimental method

X-RAY DIFFRACTION (3.07 Å)