PDBsum entry 1fpc

Hydrolase/hydrolase inhibitor

PDB id: 1fpc

Contents

Protein chains

26 a.a. *

248 a.a. *

Ligands

ASP-PHE-GLU-GLU-ILE-PRO-GLU-GLU-TYS-LEU

0ZI

Waters ×201

* Residue conservation analysis

PDB id:

1fpc

Name:

Hydrolase/hydrolase inhibitor

Title:

Active site mimetic inhibition of thrombin

Structure:

Thrombin. Chain: l. Synonym: coagulation factor ii. Thrombin. Chain: h. Synonym: coagulation factor ii. Hirudin. Chain: i. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Organ: blood. Tissue: blood. Hirudo medicinalis. Medicinal leech. Organism_taxid: 6421

Biol. unit:

Tetramer (from PQS)

Resolution:

2.30Å R-factor: 0.147

Authors:

A.Tulinsky,I.I.Mathews

Key ref:

I.I.Mathews and A.Tulinsky (1995). Active-site mimetic inhibition of thrombin. Acta Crystallogr D Biol Crystallogr, 51, 550-559. PubMed id: 15299843 DOI: 10.1107/S0907444994013132

Date:

16-Oct-94 Release date: 27-Feb-95

Protein chain

P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens

Seq: 622 a.a.

Struc: 26 a.a.

Protein chain

P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens

Seq: 622 a.a.

Struc: 248 a.a.

Enzyme reactions

• Enzyme class: Chains L, H: E.C.3.4.21.5 - thrombin.
• Reaction: Preferential cleavage: Arg-|-Gly; activates fibrinogen to fibrin and releases fibrinopeptide A and B.

DOI no: 10.1107/S0907444994013132

Acta Crystallogr D Biol Crystallogr 51:550-559 (1995)

PubMed id: 15299843

Active-site mimetic inhibition of thrombin.

I.I.Mathews, A.Tulinsky.

ABSTRACT

The structures of two mimetic inhibitor complexes of human alpha-thrombin have been determined by X-ray crystallography. One mimics a beta-turn with a bicyclic ring system; the other mimics two different active-site binding modes. The beta-turn mimetic is used to approximate a turn found in the conformation of fibrinopeptide A, which is catalytically released by thrombin in the activation of fibrinogen to fibrin. The binding of the second mimetic is a hybrid between normal substrate and the abnormal binding of the potent natural leech inhibitor hirudin. The binding of the beta-turn mimetic is tenuous, because it is like a substrate, while that of the substrate-hirudin hybrid is that of a tenacious inhibitor (which it is). Structurally retrospect modifications for rational design and improvement of both mimetic inhibitors are proposed.

Selected figure(s)

Figure 1.
Fig. 1. Thrombin peptide substrate- inhibitor complexes. The asterisk indicates sulfated tyrosine.

Figure 2.
Fig. 2. Mimetic inhibitors of thrombin. (a) FPAM, (b) DAPA, (c) FPAM 1. Special restraints applied to non-amino-acid groups during refinement to maintain geometry: arrow, bond distance; dotted, angle distance, double arrow, planar 1,4 distance and NB--B 1 --B3--B4, B2--B3--B5--NB in DAPA.

The above figures are reprinted by permission from the IUCr: Acta Crystallogr D Biol Crystallogr (1995, 51, 550-559) copyright 1995.

Figures were selected by an automated process.