7THS
Macrocyclic plasmin inhibitor
Summary for 7THS
| Entry DOI | 10.2210/pdb7ths/pdb |
| Descriptor | Plasminogen, (6S,9R,20R,23S)-N-{[4-(aminomethyl)phenyl]methyl}-20-[(benzenesulfonyl)amino]-3,13,21-trioxo-2,6,9,14,22-pentaazatetracyclo[23.2.2.2~6,9~.2~15,18~]tritriaconta-1(27),15,17,25,28,30-hexaene-23-carboxamide, SULFATE ION, ... (5 entities in total) |
| Functional Keywords | protease, inhibitor, blood clotting, hydrolase-inhibitor complex, hydrolase/inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 57019.34 |
| Authors | Guojie, W. (deposition date: 2022-01-12, release date: 2023-01-18, Last modification date: 2024-10-30) |
| Primary citation | Wiedemeyer, S.J.A.,Wu, G.,Pham, T.L.P.,Lang-Henkel, H.,Perez Urzua, B.,Whisstock, J.C.,Law, R.H.P.,Steinmetzer, T. Synthesis and Structural Characterization of Macrocyclic Plasmin Inhibitors. Chemmedchem, 18:e202200632-e202200632, 2023 Cited by PubMed Abstract: Two series of macrocyclic plasmin inhibitors with a C-terminal benzylamine group were synthesized. The substitution of the N-terminal phenylsulfonyl group of a previously described inhibitor provided two analogues with sub-nanomolar inhibition constants. Both compounds possess a high selectivity against all other tested trypsin-like serine proteases. Furthermore, a new approach was used to selectively introduce asymmetric linker segments. Two of these compounds inhibit plasmin with K values close to 2 nM. For the first time, four crystal structures of these macrocyclic inhibitors could be determined in complex with a Ser195Ala microplasmin mutant. The macrocyclic core segment of the inhibitors binds to the open active site of plasmin without any steric hindrance. This binding mode is incompatible with other trypsin-like serine proteases containing a sterically demanding 99-hairpin loop. The crystal structures obtained experimentally explain the excellent selectivity of this inhibitor type as previously hypothesized. PubMed: 36710259DOI: 10.1002/cmdc.202200632 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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