9BOT
Human mesotrypsin (PRSS3) unliganded and in autoinhibited (E*) conformation
Summary for 9BOT
| Entry DOI | 10.2210/pdb9bot/pdb |
| Related | 9BOS |
| Descriptor | Trypsin-3, SULFATE ION, CALCIUM ION, ... (6 entities in total) |
| Functional Keywords | serine protease, autoinhibited, conformational variability, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 24670.82 |
| Authors | Coban, M.,Sankaran, B.,Radisky, E.S. (deposition date: 2024-05-06, release date: 2025-06-11, Last modification date: 2025-07-16) |
| Primary citation | Coban, M.,Gokara, M.,Forero Vargas, L.M.,Tanzer, S.D.,Zhou, S.X.,Hockla, A.,Sankaran, B.,Caulfield, T.R.,Radisky, E.S. Discovery of an autoinhibited conformation in mesotrypsin reveals a strategy for selective serine protease inhibition. Sci Adv, 11:eadu9129-eadu9129, 2025 Cited by PubMed Abstract: Selective inhibition of the more than 100 S1 family serine proteases is a long-standing challenge due to their active site similarity. Mesotrypsin, implicated in cancer progression, exemplifies these difficulties; no current inhibitors achieve selectivity over other human trypsins. We found an unexpected autoinhibited conformation of mesotrypsin via x-ray crystallography, revealing a cryptic pocket adjacent to the active site. Using high-throughput virtual screening targeting this cryptic pocket, we identified a conformationally selective small-molecule inhibitor that stabilizes the inactive state of mesotrypsin. This inhibitor demonstrates selectivity for mesotrypsin over other trypsins. Our findings challenge the accepted view of digestive trypsins as constitutively active enzymes lacking potential for allosteric regulation. Furthermore, analyses of other structures suggest that dynamic sampling of closed states with analogous allosteric cryptic pockets appears widespread among S1 serine proteases. These observations point to a potentially generalizable strategy to achieve selective inhibition, offering broad implications for drug development targeting serine proteases in cancer and other diseases. PubMed: 40614191DOI: 10.1126/sciadv.adu9129 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.6 Å) |
Structure validation
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