6IWB

Crystal structure of a computationally designed protein (LD3) in complex with BCL-2

Summary for 6IWB

• Entry DOI: 10.2210/pdb6iwb/pdb
• Descriptor: Apolipoprotein E, Apoptosis regulator Bcl-2,Apoptosis regulator Bcl-2, SULFATE ION, ... (4 entities in total)
• Functional Keywords: apoptosis
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 74595.62

Authors

Kim, S.,Kwak, M.J.,Oh, B.-H.,Correia, B.E.,Gainza, P. (deposition date: 2018-12-05, release date: 2019-12-11, Last modification date: 2024-03-27)

Primary citation

Giordano-Attianese, G.,Gainza, P.,Gray-Gaillard, E.,Cribioli, E.,Shui, S.,Kim, S.,Kwak, M.J.,Vollers, S.,Corria Osorio, A.J.,Reichenbach, P.,Bonet, J.,Oh, B.H.,Irving, M.,Coukos, G.,Correia, B.E.
A computationally designed chimeric antigen receptor provides a small-molecule safety switch for T-cell therapy.
Nat.Biotechnol., 38:426-432, 2020

PubMed Abstract: Approaches to increase the activity of chimeric antigen receptor (CAR)-T cells against solid tumors may also increase the risk of toxicity and other side effects. To improve the safety of CAR-T-cell therapy, we computationally designed a chemically disruptable heterodimer (CDH) based on the binding of two human proteins. The CDH self-assembles, can be disrupted by a small-molecule drug and has a high-affinity protein interface with minimal amino acid deviation from wild-type human proteins. We incorporated the CDH into a synthetic heterodimeric CAR, called STOP-CAR, that has an antigen-recognition chain and a CD3ζ- and CD28-containing endodomain signaling chain. We tested STOP-CAR-T cells specific for two antigens in vitro and in vivo and found similar antitumor activity compared to second-generation (2G) CAR-T cells. Timed administration of the small-molecule drug dynamically inactivated the activity of STOP-CAR-T cells. Our work highlights the potential for structure-based design to add controllable elements to synthetic cellular therapies.

PubMed: 32015549
DOI: 10.1038/s41587-019-0403-9

Experimental method

X-RAY DIFFRACTION (2.5 Å)