8W2V

Solution Structure of the CD28 hinge used in chimeric antigen receptor (CAR) T-cells

8W2V の概要

• エントリーDOI: 10.2210/pdb8w2v/pdb
• NMR情報: BMRB: 31150
• 分子名称: T-cell-specific surface glycoprotein CD28 (1 entity in total)
• 機能のキーワード: car-t, cd28, immunotherapy, intrinsic disorder, immune system
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 4308.03

構造登録者

Folimonova, V.,Chen, X.,Walters, K.J. (登録日: 2024-02-21, 公開日: 2024-09-11)

主引用文献

Folimonova, V.,Chen, X.,Negi, H.,Schwieters, C.D.,Li, J.,Byrd, R.A.,Taylor, N.,Youkharibache, P.,Walters, K.J.
CD28 hinge used in chimeric antigen receptor (CAR) T-cells exhibits local structure and conformational exchange amidst global disorder.
Commun Biol, 7:1072-1072, 2024

PubMed Abstract: T-cell therapies based on chimeric antigen receptor (CAR) targeting of a tumor-specific antigen offer hope for patients with relapsed or refractory cancers. CAR hinge and transmembrane regions link antigen recognition domains to intracellular signal transduction domains. Here, we apply biophysical methods to characterize the structure and dynamic properties of the CD28 CAR hinge (CD28H) used in an FDA-approved CD19 CAR for the treatment of B-lineage leukemia/lymphoma. By using nuclear Overhauser effect spectroscopy (NOESY), which detects even transiently occupied structural motifs, we observed otherwise elusive local structural elements amidst overall disorder in CD28H, including a conformational switch from a native β-strand to a 3-helix and polyproline II helix-like structure. These local structural motifs contribute to an overall loosely formed extended geometry that could be captured by NOESY data. All FDA-approved CARs use prolines in the hinge region, which we find in CD28, and previously in CD8α, isomerize to promote structural plasticity and dynamics. These local structural elements may function in recognition and signaling events and constrain the spacing between the transmembrane and antigen recognition domains. Our study thus demonstrates a method for detecting local and transient structure within intrinsically disordered systems and moreover, our CD28H findings may inform future CAR design.

PubMed: 39217198
DOI: 10.1038/s42003-024-06770-w

実験手法

SOLUTION NMR