PDBsum entry 3r4l

Blood clotting

PDB id: 3r4l

Contents

Protein chain

377 a.a.

Ligands

NAG-NAG-BMA-BMA-FUC

NAG

Waters ×17

PDB id:

3r4l

Name:

Blood clotting

Title:

Human very long half life plasminogen activator inhibitor type-1

Structure:

Plasminogen activator inhibitor 1. Chain: a. Fragment: unp residues 24-402. Synonym: pai, pai-1, endothelial plasminogen activator inhibitor, serpin e1. Engineered: yes. Mutation: yes. Other_details: active form

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pai1, planh1, serpine1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

2.70Å R-factor: 0.212 R-free: 0.282

Authors:

J.Yang,H.Zheng,Q.Han,E.Skrzypczak-Jankun,J.Jankun

Key ref:

J.Jankun et al. (2012). Remarkable extension of PAI-1 half-life surprisingly brings no changes to its structure. Int J Mol Med, 29, 61-64. PubMed id: 21947232

Date:

17-Mar-11 Release date: 02-Nov-11

Protein chain

P05121  (PAI1_HUMAN) -  Plasminogen activator inhibitor 1 from Homo sapiens

Seq: 402 a.a.

Struc: 377 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Int J Mol Med 29:61-64 (2012)

PubMed id: 21947232

Remarkable extension of PAI-1 half-life surprisingly brings no changes to its structure.

J.Jankun, J.Yang, H.Zheng, F.Q.Han, A.Al-Senaidy, E.Skrzypczak-Jankun.

ABSTRACT

Plasminogen activator inhibitor type 1 (PAI-1) is a serpin protein, a natural inhibitor of urokinase (uPA) and tissue plasminogen activators (tPA). By inhibiting uPA it can block growth of the cancer tumors by suppressing angiogenesis, while when acting on tPA in the blood it can avert conversion of plasminogen to plasmin preventing lysis of the clot. Furthermore, blocking PAI-1 activity can protect against thrombosis. Thus PAI-1 makes great impact on human homeostasis and is desirable for clinical application. Wild-type PAI-1 (wt-PAI-1) has a short span of activity with a t1/2 of ~2 h, being spontaneously converted into a latent form. An enormous effort has been made to create a more stable molecule with >600 PAI-1 variants constructed to study its structure-function relationship. In the present study, we evaluate the structure of the active recombinant VLHL-PAI-1 (very long half life, active >700 h) which is glycosylated similarly to wt-PAI-1 at N232 and N288, with the extended reactive center loop, intact engineered -S-S-bridge (Q174C, G323C) that precludes latency without affecting structure, and can be controlled by a reducing agent to terminate activity at will. We have already proven its usefulness to control cancer in human cancer cells, as well as preventing clot lysis in human whole blood and plasma and in a mouse model. Our results demonstrate the potential therapeutic applications (topical or systemic) of this protein in the treatment of cancer, for the trauma patients to ward off an excessive blood loss, or for people with the PAI-1 deficiency, especially during surgery.