7VM5
Crystal structure of uPA in complex with 4-guanidinobenzoic acid
Summary for 7VM5
| Entry DOI | 10.2210/pdb7vm5/pdb |
| Descriptor | Urokinase-type plasminogen activator, TRIETHYLENE GLYCOL, 4-carbamimidamidobenzoic acid, ... (4 entities in total) |
| Functional Keywords | upa, serine protease, 4-guanidinobenzoic acid, hydrolase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 28044.95 |
| Authors | Jiang, L.G.,Huang, M.D. (deposition date: 2021-10-07, release date: 2022-10-12, Last modification date: 2024-10-16) |
| Primary citation | Zhou, Y.,Wu, J.,Xue, G.,Li, J.,Jiang, L.,Huang, M. Structural study of the uPA-nafamostat complex reveals a covalent inhibitory mechanism of nafamostat. Biophys.J., 121:3940-3949, 2022 Cited by PubMed Abstract: Nafamostat mesylate (NM) is a synthetic compound that inhibits various serine proteases produced during the coagulation cascade and inflammation. Previous studies showed that NM was a highly safe drug for the treatment of different cancers, but the precise functions and mechanisms of NM are not clear. In this study, we determined a series of crystal structures of NM and its hydrolysates in complex with a serine protease (urokinase-type plasminogen activator [uPA]). These structures reveal that NM was cleaved by uPA and that a hydrolyzed product (4-guanidinobenzoic acid [GBA]) remained covalently linked to Ser195 of uPA, and the other hydrolyzed product (6-amidino-2-naphthol [6A2N]) released from uPA. Strikingly, in the inactive uPA (uPA-S195A):NM structure, the 6A2N side of intact NM binds to the specific pocket of uPA. Molecular dynamics simulations and end-point binding free-energy calculations show that the conf1 of NM (6A2N as P1 group) in the uPA-S195A:NM complex may be more stable than conf2 of NM (GBA as P1 group). Moreover, in the structure of uPA:NM complex, the imidazole group of His57 flips further away from Ser195 and disrupts the stable canonical catalytic triad conformation. These results not only reveal the inhibitory mechanism of NM as an efficient serine protease inhibitor but also might provide the structural basis for the further development of serine protease inhibitors. PubMed: 36039386DOI: 10.1016/j.bpj.2022.08.034 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.97 Å) |
Structure validation
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