Design of High Affinity Binders to Convex Protein Target Sites

Area of Science:

• Protein engineering
• Computational biology
• Structural biology

Background:

• Designing protein binders for concave protein surfaces has advanced.
• Developing minibinders for convex protein targets remains a significant challenge due to shape complementarity limitations.

Approach:

• Developed a general computational strategy for designing proteins that bind convex target sites.
• Utilized geometrically matching concave scaffolds to create novel minibinders.
• Applied the approach to design binders for TGFβRII, CTLA-4, and PD-L1.

Key Points:

• Achieved low nanomolar to picomolar binding affinities after experimental optimization.
• Demonstrated potent biological activity for designed protein binders.
• Co-crystal structures validated the accuracy of computational design models for TGFβRII and CTLA-4.

Conclusions:

• The presented approach offers a versatile method for generating high-affinity protein binders.
• Successfully addressed the challenge of designing binders for convex protein targets.
• Opens new avenues for therapeutic protein design and development.