5EG4

BOVINE TRYPSIN IN COMPLEX WITH CYCLIC INHIBITOR

Summary for 5EG4

• Entry DOI: 10.2210/pdb5eg4/pdb
• Related: 4MTB
• Descriptor: Cationic trypsin, CALCIUM ION, SULFATE ION, ... (6 entities in total)
• Functional Keywords: metal-binding, digestion, hydrolase-hydrolase inhibitor complex, hydrolase
• Biological source: Bos taurus (Bovine)
• Cellular location: Secreted, extracellular space: P00760
• Total number of polymer chains: 1
• Total formula weight: 24348.49

Authors

Knoerlein, A.,Wagner, S.,Heine, A.,Steinmetzer, T.,Klebe, G. (deposition date: 2015-10-26, release date: 2016-07-13, Last modification date: 2024-11-20)

Primary citation

Hinkes, S.,Wuttke, A.,Saupe, S.M.,Ivanova, T.,Wagner, S.,Knorlein, A.,Heine, A.,Klebe, G.,Steinmetzer, T.
Optimization of Cyclic Plasmin Inhibitors: From Benzamidines to Benzylamines.
J.Med.Chem., 59:6370-6386, 2016

PubMed Abstract: New macrocyclic plasmin inhibitors based on our previously optimized P2-P3 core segment have been developed. In the first series, the P4 residue was modified, whereas the 4-amidinobenzylamide in P1 position was maintained. The originally used P4 benzylsulfonyl residue could be replaced by various sulfonyl- or urethane-like protecting groups. In the second series, the P1 benzamidine was modified and a strong potency and excellent selectivity was retained by incorporation of p-xylenediamine. Several analogues inhibit plasmin in the subnanomolar range, and their potency against related trypsin-like serine proteases including trypsin itself could be further reduced. Selected derivatives have been tested in a plasma fibrinolysis assay and are more effective than the reference inhibitor aprotinin. The crystal structure of one inhibitor was determined in complex with trypsin. The binding mode reveals a sterical clash of the inhibitor's linker segment with the 99-hairpin loop of trypsin, which is absent in plasmin.

PubMed: 27280436
DOI: 10.1021/acs.jmedchem.6b00606

Experimental method

X-RAY DIFFRACTION (1.32 Å)