8GAD

Design of High Affinity Binders to Convex Protein Target Sites.

Yang, W., Hicks, D.R., Ghosh, A., Schwartze, T.A., Conventry, B., Goreshnik, I., Allen, A., Halabiya, S.F., Kim, C.J., Hinck, C.S., Lee, D.S., Bera, A.K., Li, Z., Wang, Y., Schlichthaerle, T., Cao, L., Huang, B., Garrett, S., Gerben, S.R., Rettie, S., Heine, P., Murray, A., Edman, N., Carter, L., Stewart, L., Almo, S., Hinck, A.P., Baker, D.

(2024) bioRxiv 

• PubMed: 38746206 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1101/2024.05.01.592114
• Primary Citation of Related Structures:  
  8GAB, 8GAC, 8GAD


• PubMed Abstract: 
  

  While there has been progress in the de novo design of small globular miniproteins (50-65 residues) to bind to primarily concave regions of a target protein surface, computational design of minibinders to convex binding sites remains an outstanding challenge due to low level of overall shape complementarity. Here, we describe a general approach to generate computationally designed proteins which bind to convex target sites that employ geometrically matching concave scaffolds. We used this approach to design proteins binding to TGFβRII, CTLA-4 and PD-L1 which following experimental optimization have low nanomolar to picomolar affinities and potent biological activity. Co-crystal structures of the TGFβRII and CTLA-4 binders in complex with the receptors are in close agreement with the design models. Our approach provides a general route to generating very high affinity binders to convex protein target sites.

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Organizational Affiliation: 

Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.