7AYE
Crystal structure of the computationally designed chemically disruptable heterodimer LD6-MDM2
Summary for 7AYE
| Entry DOI | 10.2210/pdb7aye/pdb |
| Descriptor | Isoform 11 of E3 ubiquitin-protein ligase Mdm2, Thiol:disulfide interchange protein DsbD (2 entities in total) |
| Functional Keywords | chemically disruptable heterodimer (cdh), protein-protein interaction, gene and cell therapy, protein switches, protein binding |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 28722.63 |
| Authors | Yang, C.,Lau, K.,Pojer, F.,Correia, B.E. (deposition date: 2020-11-12, release date: 2021-08-18, Last modification date: 2024-10-16) |
| Primary citation | Shui, S.,Gainza, P.,Scheller, L.,Yang, C.,Kurumida, Y.,Rosset, S.,Georgeon, S.,Di Roberto, R.B.,Castellanos-Rueda, R.,Reddy, S.T.,Correia, B.E. A rational blueprint for the design of chemically-controlled protein switches. Nat Commun, 12:5754-5754, 2021 Cited by PubMed Abstract: Small-molecule responsive protein switches are crucial components to control synthetic cellular activities. However, the repertoire of small-molecule protein switches is insufficient for many applications, including those in the translational spaces, where properties such as safety, immunogenicity, drug half-life, and drug side-effects are critical. Here, we present a computational protein design strategy to repurpose drug-inhibited protein-protein interactions as OFF- and ON-switches. The designed binders and drug-receptors form chemically-disruptable heterodimers (CDH) which dissociate in the presence of small molecules. To design ON-switches, we converted the CDHs into a multi-domain architecture which we refer to as activation by inhibitor release switches (AIR) that incorporate a rationally designed drug-insensitive receptor protein. CDHs and AIRs showed excellent performance as drug responsive switches to control combinations of synthetic circuits in mammalian cells. This approach effectively expands the chemical space and logic responses in living cells and provides a blueprint to develop new ON- and OFF-switches. PubMed: 34599176DOI: 10.1038/s41467-021-25735-9 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.95 Å) |
Structure validation
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