9Z52
Crystal structure of UFC1 in complex with N-cyclohexyl-2-hydroxyl-3-aminopropanesulfonic acid (CAPS)
Summary for 9Z52
| Entry DOI | 10.2210/pdb9z52/pdb |
| Descriptor | Ubiquitin-fold modifier-conjugating enzyme 1, 3-CYCLOHEXYL-1-PROPYLSULFONIC ACID (3 entities in total) |
| Functional Keywords | e2-like ubiquitin-fold modifier conjugating enzyme 1, caps, ligand-complex, ufmylation, ligase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 20926.02 |
| Authors | |
| Primary citation | Mulligan, D.,Mai, S.,Acharya, K.,Robustelli, J.,Cuttitta, C.,Ambroise, R.,Tredup, J.,Yan, C.,Szapiel, N.,Yanchunas, J.,Newitt, J.A.,Mahon, B.P. Discovery and Characterization of a Novel Ligand-Binding Site in UFC1 Using Sulfa- and Sulfonate-Based Compounds. Biochemistry, 65:2940-2954, 2026 Cited by PubMed Abstract: UFMylation is an important biological process where proteins are post-translationally modified via the covalent attachment of the ubiquitin-like modifier (UBL), ubiquitin-fold modifier-1 (UFM1). UFMylation is analogous to ubiquitination, occurring via the transfer of UFM1 across E1-, E2-, and E3-like enzymes, represented by ubiquitin-like modifier-activating enzyme 5 (UBA5), ubiquitin-fold modifier conjugating enzyme 1 (UFC1), and UFM1-specific ligase 1 (UFL1), respectively. Recent work has shown that dysregulation of UFMylation is associated with several diseases, sparking interest in characterizing its enzymes as potential drug targets. To date, only inhibitors targeting UBA5 have been identified, but no such ligands exist for UFC1. In this study, we present the structure of UFC1 in complex with the sulfonic acid CAPS, which revealed a novel ligand-binding pocket in UFC1. Using biophysical assays, coupled with X-ray crystallographic studies of UFC1 variants, we show that binding of CAPS to UFC1 appears pH-dependent and is enhanced by Tyr42. Further, our TSA data show that other sulfa- and sulfonate-based compounds induce dose-dependent destabilization of UFC1, consistent with weak but direct interactions with the enzyme. Lastly, using a UFMylation assay, we show that CAPS, along with Tyr42, may have a limited influence on UFM1 transfer to UFC1 and, consequently, downstream UFMylation of protein substrates. Nevertheless, our data indicate that the CAPS-binding pocket may serve as a design scaffold for the development of UFC1 modulators. With UFC1 emerging as a drug target, our study provides a possible avenue for the design and development of novel UFC1-specific modulators with therapeutic potential. PubMed: 42917125DOI: 10.1021/acs.biochem.5c00701 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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