PDBsum entry: 1cea

Serine protease

PDB-id: 1cea

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PROCHECK

Protein chains

80 a.a. *

Ligands

ACA ×2

Waters ×148

* Residue conservation analysis

Tools

Clefts Calculation

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PDB id:

1cea

Name:

Serine protease

Title:

The structure of the non-covalent complex of recombinant kringle 1 domain of human plasminogen with eaca (epsilon- aminocaproic acid)

Structure:

Plasminogen. Chain: a, b. Fragment: kringle 1. Synonym: k1pg. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Organ: blood. Expressed in: escherichia coli. Expression_system_taxid: 562

UniProt:

Chains A, B: P00747 (PLMN_HUMAN)

Seq:

Struc:

Seq:

Struc:

Seq:

Struc:

Seq:

810 a.a.

Struc:

80 a.a.

Key:	PfamA domain
Secondary structure	CATH domain

Enzyme class:

E.C.3.4.21.7   [IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Reaction:

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

Resolution:

2.06Å

R-factor:

0.168

Authors:

A.Tulinsky,I.I.Mathews

Key ref:

I.I.Mathews et al. (1996). Crystal structures of the recombinant kringle 1 domain of human plasminogen in complexes with the ligands epsilon-aminocaproic acid and trans-4-(aminomethyl)cyclohexane-1-carboxylic Acid.. Biochemistry, 35, 2567-2576. [PubMed id: 8611560] [DOI: 10.1021/bi9521351]

Date:

03-Dec-95

Release date:

03-Apr-96

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Clefts

Surface

Key reference

DOI no: 10.1021/bi9521351

Biochemistry 35:2567-2576 (1996)

PubMed id: 8611560

Crystal structures of the recombinant kringle 1 domain of human plasminogen in complexes with the ligands epsilon-aminocaproic acid and trans-4-(aminomethyl)cyclohexane-1-carboxylic Acid.

I.I.Mathews, P.Vanderhoff-Hanaver, F.J.Castellino, A.Tulinsky.

ABSTRACT

The X-ray crystal structures of the complexes of the recombinant kringle 1 domain of human plasminogen (Klpg) with the ligands epsilon-aminocaproic acid (EACA) and trans-4-(aminomethyl)cyclohexane-1-carboxylic acid (AMCHA), which are representative of a class of in vivo antifibrinolytic agents, have been determined at 2.1 angstroms resolution. Each Klpg/ligand unit cell contained a dimer of the complexes, and some small differences were noted in the kringle/ligand interatomic distances within the monomeric components of the dimers. The structures obtained allowed predictions to be made of the amino acid residues of Klpg that are likely important to ligand binding. In the crystal structure, the anionic center of Klpg responsible for coordinating the amino group of the ligands is composed of both Asp54 and Asp56, and the cationic center that stabilizes binding of the carboxylate moiety of the ligands is Arg70, with a possible contribution from Arg34. A hydrogen bond between the carboxylate of the ligand to the hydroxyl group of Tyr63 also appears to contribute to the kringle/ligand binding energies. The methylene groups of the ligand are stablized in the binding pocket by van der Waals contacts with side-chain atoms of Trp61 and Tyr71. These conclusions are in general agreement with site-directed mutagenesis results that implicate many of the same amino acid residues in the binding process, thus showing that the crystal and solution structures are in basic accord with each other. Further comparisons of the X-ray crystal structures of the Klpg/ligand complexes with each other and with apo-Klpg show that while small differences in Klpg side-chain geometries may exist in the three structures, the binding pocket can be considered to be preformed in the apokringle and not substantially altered by the nature of the omega-amino acid ligand that is inserted into the site. From the similar geometries of the binding of EACA and AMCHA, it appears that the kon is an important component to the tighter binding of AMCHA to Klpg, as compared to EACA. Ordered solvation effects of the bound AMCHA may contribute to its longer lifetime on Klpg, thereby retarding koff, both effects thus accounting for the higher binding energy of AMCHA as compared to EACA.