PDBsum entry 5ugd

Hydrolase/inhibitor

PDB id: 5ugd

Contents

Protein chain

246 a.a.

Ligands

89S

Waters ×266

PDB id:

5ugd

Name:

Hydrolase/inhibitor

Title:

Protease inhibitor

Structure:

Plasminogen. Chain: a. Fragment: unp residues 562-810. Synonym: microplasmin. Engineered: yes. Other_details: serine protease domain of plasmin

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: plg. Expressed in: komagataella phaffii gs115. Expression_system_taxid: 644223.

Resolution:

1.38Å R-factor: 0.161 R-free: 0.182

Authors:

R.H.P.Law,G.Wu,J.C.Whisstock

Key ref:

R.H.P.Law et al. (2017). X-ray crystal structure of plasmin with tranexamic acid-derived active site inhibitors. Blood Adv, 1, 766-771. PubMed id: 29296720

Date:

08-Jan-17 Release date: 31-May-17

Protein chain

P00747  (PLMN_HUMAN) -  Plasminogen from Homo sapiens

Seq: 810 a.a.

Struc: 246 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.21.7 - plasmin.
• Reaction: Preferential cleavage: Lys-|-Xaa > Arg-|-Xaa; higher selectivity than trypsin. Converts fibrin into soluble products.

Blood Adv 1:766-771 (2017)

PubMed id: 29296720

X-ray crystal structure of plasmin with tranexamic acid-derived active site inhibitors.

R.H.P.Law, G.Wu, E.W.W.Leung, K.Hidaka, A.J.Quek, T.T.Caradoc-Davies, D.Jeevarajah, P.J.Conroy, N.M.Kirby, R.S.Norton, Y.Tsuda, J.C.Whisstock.

ABSTRACT

The zymogen protease plasminogen and its active form plasmin perform key roles in blood clot dissolution, tissue remodeling, cell migration, and bacterial pathogenesis. Dysregulation of the plasminogen/plasmin system results in life-threatening hemorrhagic disorders or thrombotic vascular occlusion. Accordingly, inhibitors of this system are clinically important. Currently, tranexamic acid (TXA), a molecule that prevents plasminogen activation through blocking recruitment to target substrates, is the most widely used inhibitor for the plasminogen/plasmin system in therapeutics. However, TXA lacks efficacy on the active form of plasmin. Thus, there is a need to develop specific inhibitors that target the protease active site. Here we report the crystal structures of plasmin in complex with the novel YO (trans-4-aminomethylcyclohexanecarbonyl-l-tyrosine-n-octylamide) class of small molecule inhibitors. We found that these inhibitors form key interactions with the S1 and S3' subsites of the catalytic cleft. Here, the TXA moiety of the YO compounds inserts into the primary (S1) specificity pocket, suggesting that TXA itself may function as a weak plasmin inhibitor, a hypothesis supported by subsequent biochemical and biophysical analyses. Mutational studies reveal that F587 of the S' subsite plays a key role in mediating the inhibitor interaction. Taken together, these data provide a foundation for the future development of small molecule inhibitors to specifically regulate plasmin function in a range of diseases and disorders.