6V67

Apo Structure of the De Novo PD-1 Binding Miniprotein GR918.2

6V67 の概要

• エントリーDOI: 10.2210/pdb6v67/pdb
• 分子名称: PD-1 Binding Miniprotein GR918.2 (2 entities in total)
• 機能のキーワード: pd-1, disulfide miniprotein, computational design, binder, de novo protein
• 由来する生物種: synthetic construct
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 9879.20

構造登録者

Bick, M.J.,Bryan, C.M.,Baker, D.,Dimaio, F.,Kang, A. (登録日: 2019-12-04, 公開日: 2020-12-09, 最終更新日: 2024-10-23)

主引用文献

Bryan, C.M.,Rocklin, G.J.,Bick, M.J.,Ford, A.,Majri-Morrison, S.,Kroll, A.V.,Miller, C.J.,Carter, L.,Goreshnik, I.,Kang, A.,DiMaio, F.,Tarbell, K.V.,Baker, D.
Computational design of a synthetic PD-1 agonist.
Proc.Natl.Acad.Sci.USA, 118:-, 2021

PubMed Abstract: Programmed cell death protein-1 (PD-1) expressed on activated T cells inhibits T cell function and proliferation to prevent an excessive immune response, and disease can result if this delicate balance is shifted in either direction. Tumor cells often take advantage of this pathway by overexpressing the PD-1 ligand PD-L1 to evade destruction by the immune system. Alternatively, if there is a decrease in function of the PD-1 pathway, unchecked activation of the immune system and autoimmunity can result. Using a combination of computation and experiment, we designed a hyperstable 40-residue miniprotein, PD-MP1, that specifically binds murine and human PD-1 at the PD-L1 interface with a K of ∼100 nM. The apo crystal structure shows that the binder folds as designed with a backbone RMSD of 1.3 Å to the design model. Trimerization of PD-MP1 resulted in a PD-1 agonist that strongly inhibits murine T cell activation. This small, hyperstable PD-1 binding protein was computationally designed with an all-beta interface, and the trimeric agonist could contribute to treatments for autoimmune and inflammatory diseases.

PubMed: 34272285
DOI: 10.1073/pnas.2102164118

実験手法

X-RAY DIFFRACTION (1.07 Å)