Interleukin-2 superkines by computational design

Author:

Ren Junming12ORCID,Chu Alexander E.34ORCID,Jude Kevin M.12ORCID,Picton Lora K.12,Kare Aris J.3ORCID,Su Leon12ORCID,Montano Romero Alejandra3ORCID,Huang Po-Ssu34ORCID,Garcia K. Christopher125

Affiliation:

1. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305

2. HHMI, Stanford University School of Medicine, Stanford, CA 94305

3. Department of Bioengineering, Stanford University, Stanford, CA 94305

4. Biophysics Program, Stanford University, Stanford, CA 94305

5. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305

Abstract

SignificanceWhile computational engineering of therapeutic proteins is a desirable goal, in practice the optimization of protein–protein interactions requires substantial experimental intervention. We present here a computational approach that focuses on stabilizing core protein structures rather than engineering the protein–protein interface. Using this approach, we designed thermostabilized interleukin-2 (IL-2) variants that bind tightly to their receptor without experimental optimization, mimicking the properties of the yeast-display engineered IL-2 variant “super-2.” Our results suggest that structure-guided stabilization may be a general method for in silico affinity maturation of protein–protein interactions.

Funder

HHS | National Institutes of Health

Howard Hughes Medical Institute

Ludwig Institute for Cancer Research

G. Harold and Leila Y. Mathers Charitable Foundation

U.S. Department of Energy

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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