PDBsum entry 4cik

Hydrolase

PDB id

4cik

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Contents

			Protein chain

					81 a.a.

			Ligands

					XO3

			Waters ×183

PDB id:

4cik

Links

Name:

Hydrolase

Title:

Plasminogen kringle 1 in complex with inhibitor

Structure:

Plasminogen. Chain: a. Fragment: kringle 1, residues 101-181. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: komagataella pastoris. Expression_system_taxid: 4922

Resolution:

1.78Å

R-factor:

0.253

R-free:

0.292

Authors:

Y.Xue,C.Johansson,L.Cheng,D.Pettersen,D.Gustafsson

Key ref:

L.Cheng et al. (2014). Discovery of the Fibrinolysis Inhibitor AZD6564, Acting via Interference of a Protein-Protein Interaction. Acs Med Chem Lett, 5, 538-543. PubMed id: 24900876 DOI: 10.1021/ml400526d

Date:

10-Dec-13

Release date:

18-Jun-14

PROCHECK

	Headers

	References

Protein chain

P00747 (PLMN_HUMAN) - Plasminogen from Homo sapiens

Seq: Struc:

Seq: Struc:					810 a.a. 81 a.a.

Key:

PfamA domain

Secondary structure

CATH domain



		Enzyme reactions

Enzyme class:

E.C.3.4.21.7 - plasmin.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

Reaction:

Preferential cleavage: Lys-|-Xaa > Arg-|-Xaa; higher selectivity than trypsin. Converts fibrin into soluble products.

DOI no: 10.1021/ml400526d	Acs Med Chem Lett 5:538-543 (2014)
PubMed id: 24900876

Discovery of the Fibrinolysis Inhibitor AZD6564, Acting via Interference of a Protein-Protein Interaction.
L.Cheng, D.Pettersen, B.Ohlsson, P.Schell, M.Karle, E.Evertsson, S.Pahlén, M.Jonforsen, A.T.Plowright, J.Boström, T.Fex, A.Thelin, C.Hilgendorf, Y.Xue, G.Wahlund, W.Lindberg, L.O.Larsson, D.Gustafsson.

ABSTRACT

A class of novel oral fibrinolysis inhibitors has been discovered, which are lysine mimetics containing an isoxazolone as a carboxylic acid isostere. As evidenced by X-ray crystallography the inhibitors bind to the lysine binding site in plasmin thus preventing plasmin from binding to fibrin, hence blocking the protein-protein interaction. Optimization of the series, focusing on potency in human buffer and plasma clotlysis assays, permeability, and GABAa selectivity, led to the discovery of AZD6564 (19) displaying an in vitro human plasma clot lysis IC50 of 0.44 μM, no detectable activity against GABAa, and with DMPK properties leading to a predicted dose of 340 mg twice a day oral dosing in humans.