Nine New TRIM PRYSPRY Structures Uncover Key Drug Design Challenges

My colleagues from The Structural Genomics Consortium (SGC) (Rezart Zhubi, Andreas C. Joerger, Stefan Knapp) just published a paper “𝐒𝐭𝐫𝐮𝐜𝐭𝐮𝐫𝐚𝐥 𝐚𝐧𝐚𝐥𝐲𝐬𝐢𝐬 𝐨𝐟 𝐓𝐑𝐈𝐌 𝐟𝐚𝐦𝐢𝐥𝐲 𝐏𝐑𝐘𝐒𝐏𝐑𝐘 𝐝𝐨𝐦𝐚𝐢𝐧𝐬 𝐚𝐧𝐝 𝐢𝐭𝐬 𝐢𝐦𝐩𝐥𝐢𝐜𝐚𝐭𝐢𝐨𝐧𝐬 𝐟𝐨𝐫 𝐄3-𝐥𝐢𝐠𝐚𝐧𝐝 𝐝𝐞𝐬𝐢𝐠𝐧” that discusses 9 new X-ray structures, providing valuable structural insights for this family of E3 ligases.

🔑 Key Structural Findings:
✅ Conserved β-sandwich fold across family members despite low sequence conservation
✅ Significant loop variations flanking canonical substrate-binding sites modulate pocket shape and electrostatics
✅ TRIM36 dimerization partially occludes substrate-binding site through unique β-strand insertion
✅ TRIM11 subdomain swapping reveals increased structural plasticity in β-strands 7–8

💊 Druggability Assessment:
✅ While small-molecule ligands remain feasible (as demonstrated for TRIM58, TRIM21, TRIM24, and TRIM7), developing high-affinity binders will be particularly challenging for family members with collapsed or shallow pockets
✅ Conventional pocket analysis failed to detect sizeable pockets for some TRIM members (e.g., TRIM16)
✅ In some cases, such as MID2, it may be possible to target transient protein states with more open pockets, provided these states are sufficiently populated in solution
✅ The overall structural divergence of the canonical substrate-binding site is illustrated by the permutation of tryptophan residues, potential interaction hotspots, across the binding site in different family members

Which TRIM protein would you target next❓

Which TRIM protein is most interesting for you in the context of PROTAC development or therapeutic potential❓

Full article: https://www.sciencedirect.com/science/article/pii/S2590152425000157

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📝 Related story:
If you’d like to see how we developed a small-molecule ligand for TRIM7, check out our earlier publication here.

#StructuralBiology #DrugDiscovery #TRIMProteins #TPD #MedicinalChemistry #PROTACs #E3Ligases