8X7H
Crystal structure of the ternary complex of GID4-PROTAC(NEP162)-BRD4(BD1).
Summary for 8X7H
| Entry DOI | 10.2210/pdb8x7h/pdb |
| Descriptor | Glucose-induced degradation protein 4 homolog, Bromodomain-containing protein 4, ~{N}-[4-[6-[3-[4-[2-[(9~{S})-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0^{2,6}]trideca-2(6),4,7,10,12-pentaen-9-yl]ethanoyl]piperazin-1-yl]propoxy]-1~{H}-benzimidazol-2-yl]cyclohexyl]-2-(1~{H}-indol-2-ylmethylamino)ethanamide, ... (5 entities in total) |
| Functional Keywords | ubiquitin ligase, cytosolic protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 8 |
| Total formula weight | 142614.76 |
| Authors | |
| Primary citation | Li, Y.,Bao, K.,Sun, J.,Ge, R.,Zhang, Q.,Zhang, B.,Yan, X.,Li, J.,Shi, F.,Zhang, M.,Zang, J.,Liu, M.,Zhou, J.,Mi, W.,Xie, S.,Chen, D.,Shi, L.,Dong, C. Design of PROTACs utilizing the E3 ligase GID4 for targeted protein degradation. Nat.Struct.Mol.Biol., 32:1825-1837, 2025 Cited by PubMed Abstract: Proteolysis targeting chimeras (PROTACs) hijack E3 ligases and the ubiquitin-proteasome system to achieve selective degradation of neo-substrates. Their ability to target otherwise intractable substrates has rendered them a valuable modality in drug discovery. However, only a handful of over 600 human E3 ligases have been functionalized for PROTAC applications. Here we show that the E3 ligase GID4 (glucose-induced degradation deficient complex 4) can be leveraged for targeted protein degradation using a noncovalent small molecule. We design and synthesize GID4-based PROTACs, exemplified by NEP162, which can eliminate endogenous BRD4 in a GID4- and ubiquitin-proteasome system-dependent manner. NEP162 exhibits antiproliferative activity and inhibits tumor growth in a xenograft model, hinting toward potential anticancer applications. We further present the crystal structures of GID4-PROTAC-BRD4 ternary complexes in three distinct states, unveiling plastic interactions between GID4 and BRD4. These structural insights, combined with in vitro and in vivo data, decipher the molecular basis by which the hereby developed PROTACs recruit BRD4 to GID4 for targeted degradation and expand our arsenal of PROTAC-exploitable E3 ligases. PubMed: 40295770DOI: 10.1038/s41594-025-01537-1 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.9 Å) |
Structure validation
Download full validation report
