6Y07

Designing a Granulopoietic Protein by Topological Rescaffolding 1: Sohair

Summary for 6Y07

• Entry DOI: 10.2210/pdb6y07/pdb
• NMR Information: BMRB: 34489
• Descriptor: sohair (1 entity in total)
• Functional Keywords: protein design, receptor modulator, gcsf analog, de novo protein
• Biological source: synthetic construct
• Total number of polymer chains: 1
• Total formula weight: 20297.09

Authors

ElGamacy, M.,Coles, M. (deposition date: 2020-02-06, release date: 2020-03-18, Last modification date: 2024-05-15)

Primary citation

Hernandez Alvarez, B.,Skokowa, J.,Coles, M.,Mir, P.,Nasri, M.,Maksymenko, K.,Weidmann, L.,Rogers, K.W.,Welte, K.,Lupas, A.N.,Muller, P.,ElGamacy, M.
Design of novel granulopoietic proteins by topological rescaffolding.
Plos Biol., 18:e3000919-e3000919, 2020

PubMed Abstract: Computational protein design is rapidly becoming more powerful, and improving the accuracy of computational methods would greatly streamline protein engineering by eliminating the need for empirical optimization in the laboratory. In this work, we set out to design novel granulopoietic agents using a rescaffolding strategy with the goal of achieving simpler and more stable proteins. All of the 4 experimentally tested designs were folded, monomeric, and stable, while the 2 determined structures agreed with the design models within less than 2.5 Å. Despite the lack of significant topological or sequence similarity to their natural granulopoietic counterpart, 2 designs bound to the granulocyte colony-stimulating factor (G-CSF) receptor and exhibited potent, but delayed, in vitro proliferative activity in a G-CSF-dependent cell line. Interestingly, the designs also induced proliferation and differentiation of primary human hematopoietic stem cells into mature granulocytes, highlighting the utility of our approach to develop highly active therapeutic leads purely based on computational design.

PubMed: 33351791
DOI: 10.1371/journal.pbio.3000919

Experimental method

SOLUTION NMR