7RAA

Designed StabIL-2 seq15

7RAA の概要

• エントリーDOI: 10.2210/pdb7raa/pdb
• 分子名称: Interleukin-2, MAGNESIUM ION (3 entities in total)
• 機能のキーワード: computational design, cytokine
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 62392.87

構造登録者

Jude, K.M.,Chu, A.E.,Huang, P.-S.,Garcia, K.C. (登録日: 2021-06-30, 公開日: 2022-03-16, 最終更新日: 2024-10-16)

主引用文献

Ren, J.,Chu, A.E.,Jude, K.M.,Picton, L.K.,Kare, A.J.,Su, L.,Montano Romero, A.,Huang, P.S.,Garcia, K.C.
Interleukin-2 superkines by computational design.
Proc.Natl.Acad.Sci.USA, 119:e2117401119-e2117401119, 2022

PubMed Abstract: Affinity maturation of protein–protein interactions is an important approach in the development of therapeutic proteins such as cytokines. Typical experimental strategies involve targeting the cytokine-receptor interface with combinatorial libraries and then selecting for higher-affinity variants. Mutations to the binding scaffold are usually not considered main drivers for improved affinity. Here we demonstrate that computational design can provide affinity-enhanced variants of interleukin-2 (IL-2) “out of the box” without any requirement for interface engineering. Using a strategy of global IL-2 structural stabilization targeting metastable regions of the three-dimensional structure, rather than the receptor binding interfaces, we computationally designed thermostable IL-2 variants with up to 40-fold higher affinity for IL-2Rβ without any library-based optimization. These IL-2 analogs exhibited CD25-independent activities on T and natural killer (NK) cells both in vitro and in vivo, mimicking the properties of the IL-2 superkine “super-2” that was engineered through yeast surface display [A. M. Levin et al., Nature, 484, 529–533 (2012)]. Structure-guided stabilization of cytokines is a powerful approach to affinity maturation with applications to many cytokine and protein–protein interactions.

PubMed: 35294290
DOI: 10.1073/pnas.2117401119

実験手法

X-RAY DIFFRACTION (2.69 Å)