9R11

Structure of the PRYSPRY domain of human MID2, crystal form II

Summary for 9R11

• Entry DOI: 10.2210/pdb9r11/pdb
• Descriptor: Probable E3 ubiquitin-protein ligase MID2, 1,2-ETHANEDIOL, (4S)-2-METHYL-2,4-PENTANEDIOL, ... (4 entities in total)
• Functional Keywords: trim family, mid2, trim1, b30.2 domain, spry domain, pryspry domain, e3 ubiquitin ligase, ligase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 43437.58

Authors

Munoz Sosa, C.J.,Zhubi, R.,Chaikuad, A.,Knapp, S.,Joerger, A.C.,Structural Genomics Consortium (SGC) (deposition date: 2025-04-24, release date: 2025-09-10)

Primary citation

Zhubi, R.,Chaikuad, A.,Munoz Sosa, C.J.,Joerger, A.C.,Knapp, S.
Structural analysis of TRIM family PRYSPRY domains and its implications for E3-ligand design.
J Struct Biol X, 12:100134-100134, 2025

PubMed Abstract: Tripartite motif (TRIM) proteins constitute one of the largest subfamilies of RING-type E3 ubiquitin ligases and are attractive targets for the development of novel degraders that exploit the ubiquitin-proteasome pathway. More than half of all TRIM family members contain a PRYSPRY domain, a potentially druggable protein interaction module, located in their C-terminal region. Here, we have determined crystal structures of the PRYSPRY domains from nine TRIM family proteins: TRIM1 (MID2), TRIM9, TRIM10, TRIM11, TRIM15, TRIM16, TRIM18 (MID1), TRIM36, and TRIM67. These structures reveal conservation of the overall β-sandwich topology, despite low sequence conservation, with a unique subdomain swap observed in TRIM11. Significant variations were found in the loops flanking the canonical substrate-binding site, which modulate the shape and electrostatic properties of the binding pocket, hinting at substantial differences in substrate specificity and binding modes among family members. TRIM36 features a unique structural motif between the canonical β-strands 2 and 3, leading to the formation of a dimer, with the canonical substrate-binding site partially occluded by the dimerization motif. In addition, we mapped the locations of missense mutations in MID1 associated with X-linked Opitz syndrome, suggesting that some of these mutations impair the conformational stability of the protein. Taken together, our data provide intriguing insights into the structural and functional divergence of TRIM family PRYSPRY domains, their potential druggability and substrate recognition, and the challenges of ligand design.

PubMed: 40821731
DOI: 10.1016/j.yjsbx.2025.100134

Experimental method

X-RAY DIFFRACTION (1.64 Å)