PDBsum entry 4g8r

Blood clotting/inhibitor

PDB id: 4g8r

Contents

Protein chains

357 a.a.

Ligands

SO4

96P ×2

Waters ×224

PDB id:

4g8r

Name:

Blood clotting/inhibitor

Title:

Crystal structure of a novel small molecule inactivator bound to plasminogen activator inhibitor-1

Structure:

Plasminogen activator inhibitor-1. Chain: a, b. Fragment: unp residues 28-402. Synonym: pai, pai-1, endothelial plasminogen activator inhibitor, serpin e1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pai-1, pai1, planh1, serpine1. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.19Å R-factor: 0.177 R-free: 0.215

Authors:

J.A.Stuckey,D.A.Lawrence,S.-H.Li

Key ref:

S.H.Li et al. (2013). Mechanistic characterization and crystal structure of a small molecule inactivator bound to plasminogen activator inhibitor-1. Proc Natl Acad Sci U S A, 110, E4941. PubMed id: 24297881 DOI: 10.1073/pnas.1216499110

Date:

23-Jul-12 Release date: 25-Dec-13

Protein chains

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

Seq: 402 a.a.

Struc: 357 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1073/pnas.1216499110

Proc Natl Acad Sci U S A 110:E4941 (2013)

PubMed id: 24297881

Mechanistic characterization and crystal structure of a small molecule inactivator bound to plasminogen activator inhibitor-1.

S.H.Li, A.A.Reinke, K.L.Sanders, C.D.Emal, J.C.Whisstock, J.A.Stuckey, D.A.Lawrence.

ABSTRACT

Plasminogen activator inhibitor type-1 (PAI-1) is a member of the serine protease inhibitor (serpin) family. Excessive PAI-1 activity is associated with human disease, making it an attractive pharmaceutical target. However, like other serpins, PAI-1 has a labile structure, making it a difficult target for the development of small molecule inhibitors, and to date, there are no US Food and Drug Administration-approved small molecule inactivators of any serpins. Here we describe the mechanistic and structural characterization of a high affinity inactivator of PAI-1. This molecule binds to PAI-1 reversibly and acts through an allosteric mechanism that inhibits PAI-1 binding to proteases and to its cofactor vitronectin. The binding site is identified by X-ray crystallography and mutagenesis as a pocket at the interface of β-sheets B and C and α-helix H. A similar pocket is present on other serpins, suggesting that this site could be a common target in this structurally conserved protein family.