9BCC

Structure of KLHDC2 bound to SJ46418

This is a non-PDB format compatible entry.

Summary for 9BCC

• Entry DOI: 10.2210/pdb9bcc/pdb
• Related: 9BC9
• Descriptor: Kelch domain-containing protein 2, N-({2-[8-(2-methoxyethoxy)naphthalen-2-yl]-1,3-thiazol-4-yl}acetyl)glycine, COBALT HEXAMMINE(III), ... (4 entities in total)
• Functional Keywords: kelch domain, inhibitor, complex, klhdc2, ligase, ligase-inhibitor complex, ligase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 80490.86

Authors

Scott, D.C.,Dharuman, S.,Griffith, E.,Chai, S.C.,Ronnebaum, J.,King, M.T.,Tangallapally, R.,Lee, C.,Gee, C.T.,Lee, H.W.,Ochoada, J.,Miller, D.J.,Jayasinghe, T.,Paulo, J.A.,Elledge, S.J.,Harper, J.W.,Chen, T.,Lee, R.E.,Schulman, B.A. (deposition date: 2024-04-08, release date: 2024-11-06, Last modification date: 2025-03-05)

Primary citation

Scott, D.C.,Dharuman, S.,Griffith, E.,Chai, S.C.,Ronnebaum, J.,King, M.T.,Tangallapally, R.,Lee, C.,Gee, C.T.,Yang, L.,Li, Y.,Loudon, V.C.,Lee, H.W.,Ochoada, J.,Miller, D.J.,Jayasinghe, T.,Paulo, J.A.,Elledge, S.J.,Harper, J.W.,Chen, T.,Lee, R.E.,Schulman, B.A.
Principles of paralog-specific targeted protein degradation engaging the C-degron E3 KLHDC2.
Nat Commun, 15:8829-8829, 2024

PubMed Abstract: PROTAC® (proteolysis-targeting chimera) molecules induce proximity between an E3 ligase and protein-of-interest (POI) to target the POI for ubiquitin-mediated degradation. Cooperative E3-PROTAC-POI complexes have potential to achieve neo-substrate selectivity beyond that established by POI binding to the ligand alone. Here, we extend the collection of ubiquitin ligases employable for cooperative ternary complex formation to include the C-degron E3 KLHDC2. Ligands were identified that engage the C-degron binding site in KLHDC2, subjected to structure-based improvement, and linked to JQ1 for BET-family neo-substrate recruitment. Consideration of the exit vector emanating from the ligand engaged in KLHDC2's U-shaped degron-binding pocket enabled generation of SJ46421, which drives formation of a remarkably cooperative, paralog-selective ternary complex with BRD3. Meanwhile, screening pro-drug variants enabled surmounting cell permeability limitations imposed by acidic moieties resembling the KLHDC2-binding C-degron. Selectivity for BRD3 compared to other BET-family members is further manifested in ubiquitylation in vitro, and prodrug version SJ46420-mediated degradation in cells. Selectivity is also achieved for the ubiquitin ligase, overcoming E3 auto-inhibition to engage KLHDC2, but not the related KLHDC1, KLHDC3, or KLHDC10 E3s. In sum, our study establishes neo-substrate-specific targeted protein degradation via KLHDC2, and provides a framework for developing selective PROTAC protein degraders employing C-degron E3 ligases.

PubMed: 39396041
DOI: 10.1038/s41467-024-52966-3

Experimental method

X-RAY DIFFRACTION (1.7 Å)