6SIS
Crystal structure of macrocyclic PROTAC 1 in complex with the second bromodomain of human Brd4 and pVHL:ElonginC:ElonginB
Summary for 6SIS
| Entry DOI | 10.2210/pdb6sis/pdb |
| Descriptor | Bromodomain-containing protein 4, Elongin-B, Elongin-C, ... (6 entities in total) |
| Functional Keywords | protac complex, macrocycle, targeted degradation, ligase |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 8 |
| Total formula weight | 115212.83 |
| Authors | Hughes, S.J.,Testa, A.,Ciulli, A. (deposition date: 2019-08-10, release date: 2019-12-04, Last modification date: 2024-01-24) |
| Primary citation | Testa, A.,Hughes, S.J.,Lucas, X.,Wright, J.E.,Ciulli, A. Structure-Based Design of a Macrocyclic PROTAC. Angew.Chem.Int.Ed.Engl., 59:1727-1734, 2020 Cited by PubMed Abstract: Constraining a molecule in its bioactive conformation via macrocyclization represents an attractive strategy to rationally design functional chemical probes. While this approach has been applied to enzyme inhibitors or receptor antagonists, to date it remains unprecedented for bifunctional molecules that bring proteins together, such as PROTAC degraders. Herein, we report the design and synthesis of a macrocyclic PROTAC by adding a cyclizing linker to the BET degrader MZ1. A co-crystal structure of macroPROTAC-1 bound in a ternary complex with VHL and the second bromodomain of Brd4 validated the rational design. Biophysical studies revealed enhanced discrimination between the second and the first bromodomains of BET proteins. Despite a 12-fold loss of binary binding affinity for Brd4, macroPROTAC-1 exhibited cellular activity comparable to MZ1. Our findings support macrocyclization as an advantageous strategy to enhance PROTAC degradation potency and selectivity between homologous targets. PubMed: 31746102DOI: 10.1002/anie.201914396 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.5 Å) |
Structure validation
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