{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T12:56:08Z","timestamp":1791291368888,"version":"4.3.0"},"reference-count":49,"publisher":"American Chemical Society (ACS)","issue":"19","license":[{"start":{"date-parts":[[2027,9,3]],"date-time":"2027-09-03T00:00:00Z","timestamp":1819929600000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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.<\/jats:p>","DOI":"10.1021\/acs.biochem.5c00701","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T01:02:04Z","timestamp":1788483724000},"page":"2940-2954","source":"Crossref","is-referenced-by-count":0,"title":["Discovery and\nCharacterization of a Novel Ligand-Binding\nSite in UFC1 Using Sulfa- and Sulfonate-Based Compounds"],"prefix":"10.1021","volume":"65","author":[{"given":"Dawn","family":"Mulligan","sequence":"first","affiliation":[{"name":"Bristol Myers Squibb , , PO Box 4000, , ,","place":["Princeton, New Jersey, United States, 08543"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Selyna","family":"Mai","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb , , PO Box 4000, , ,","place":["Princeton, New Jersey, United States, 08543"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kriti","family":"Acharya","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb , , PO Box 4000, , ,","place":["Princeton, New Jersey, United States, 08543"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaclyn","family":"Robustelli","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb , , PO Box 4000, , ,","place":["Princeton, New Jersey, United States, 08543"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Cuttitta","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb , , PO Box 4000, , ,","place":["Princeton, New Jersey, United States, 08543"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Re\u0301ginald","family":"Ambroise","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb , , PO Box 4000, , ,","place":["Princeton, New Jersey, United States, 08543"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Tredup","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb , , PO Box 4000, , ,","place":["Princeton, New Jersey, United States, 08543"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunhong","family":"Yan","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb , , PO Box 4000, , ,","place":["Princeton, New Jersey, United States, 08543"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Szapiel","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb , , PO Box 4000, , ,","place":["Princeton, New Jersey, United States, 08543"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Yanchunas","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb , , PO Box 4000, , ,","place":["Princeton, New Jersey, United States, 08543"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A.","family":"Newitt","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb , , PO Box 4000, , ,","place":["Princeton, New Jersey, United States, 08543"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5571-8058","authenticated-orcid":true,"given":"Brian P.","family":"Mahon","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb , , PO Box 4000, , ,","place":["Princeton, New Jersey, United States, 08543"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"2026100608071437700_cit1","doi-asserted-by":"publisher","DOI":"10.3390\/cells12212543","article-title":"The Post-Translational Role of UFMylation in Physiology\nand Disease","volume":"12","author":"Wang","year":"2023","journal-title":"Cells"},{"key":"2026100608071437700_cit2","doi-asserted-by":"publisher","first-page":"5040","DOI":"10.1111\/febs.16730","article-title":"A guide to\nUFMylation, an emerging\nposttranslational modification","volume":"290","author":"Millrine","year":"2023","journal-title":"FEBS J."},{"key":"2026100608071437700_cit3","doi-asserted-by":"publisher","DOI":"10.3390\/biom10101442","article-title":"Decrypting\nUFMylation: How Proteins\nAre Modified with UFM1","volume":"10","author":"Banerjee","year":"2020","journal-title":"Biomolecules"},{"key":"2026100608071437700_cit4","doi-asserted-by":"publisher","first-page":"5256","DOI":"10.1074\/jbc.M610590200","article-title":"Two Novel\nUbiquitin-fold Modifier\n1 (Ufm1)-specific Proteases, UfSP1 and UfSP2","volume":"282","author":"Kang","year":"2007","journal-title":"J. Biol. Chem."},{"key":"2026100608071437700_cit5","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1038\/nature07958","article-title":"Origin and\nfunction of ubiquitin-like proteins","volume":"458","author":"Hochstrasser","year":"2009","journal-title":"Nature"},{"key":"2026100608071437700_cit6","doi-asserted-by":"publisher","first-page":"1977","DOI":"10.1038\/sj.emboj.7600205","article-title":"A novel protein-conjugating\nsystem for Ufm1, a ubiquitin-fold\nmodifier","volume":"23","author":"Komatsu","year":"2004","journal-title":"EMBO J."},{"key":"2026100608071437700_cit7","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09175-0","article-title":"UFL1 promotes histone H4 ufmylation\nand ATM activation","volume":"10","author":"Qin","year":"2019","journal-title":"Nat. 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