PDBsum entry 1oc0

Hydrolase/inhibitor

PDB id: 1oc0

Contents

Protein chains

364 a.a. *

37 a.a. *

Waters ×137

* Residue conservation analysis

PDB id:

1oc0

Name:

Hydrolase/inhibitor

Title:

Plasminogen activator inhibitor-1 complex with somatomedin b domain of vitronectin

Structure:

Plasminogen activator inhibitor-1. Chain: a. Synonym: endothelial plasminogen activator inhibitor, pai-1, pai. Engineered: yes. Mutation: yes. Vitronectin. Chain: b. Fragment: somatomedin b, residues 20-70. Synonym: serum spreading factor, s-protein, s75.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Tissue: blood. Expressed in: escherichia coli. Expression_system_taxid: 469008. Expression_system_taxid: 562. Other_details: obtained by cnbr cleavage of fusion protein

Biol. unit:

Dimer (from PDB file)

Resolution:

2.28Å R-factor: 0.198 R-free: 0.252

Authors:

R.J.Read,A.Zhou,J.A.Huntington,N.S.Pannu,R.W.Carrell

Key ref:

A.Zhou et al. (2003). How vitronectin binds PAI-1 to modulate fibrinolysis and cell migration. Nat Struct Biol, 10, 541-544. PubMed id: 12808446 DOI: 10.1038/nsb943

Date:

03-Feb-03 Release date: 19-Jun-03

Protein chain

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

Seq: 402 a.a.

Struc: 364 a.a.*

Protein chain

P04004  (VTNC_HUMAN) -  Vitronectin from Homo sapiens

Seq: 478 a.a.

Struc: 37 a.a.

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

DOI no: 10.1038/nsb943

Nat Struct Biol 10:541-544 (2003)

PubMed id: 12808446

How vitronectin binds PAI-1 to modulate fibrinolysis and cell migration.

A.Zhou, J.A.Huntington, N.S.Pannu, R.W.Carrell, R.J.Read.

ABSTRACT

The interaction of the plasma protein vitronectin with plasminogen activator inhibitor-1 (PAI-1) is central to human health. Vitronectin binding extends the lifetime of active PAI-1, which controls hemostasis by inhibiting fibrinolysis and has also been implicated in angiogenesis. The PAI-1-vitronectin binding interaction also affects cell adhesion and motility. For these reasons, elevated PAI-1 activities are associated both with coronary thrombosis and with a poor prognosis in many cancers. Here we show the crystal structure at a resolution of 2.3 A of the complex of the somatomedin B domain of vitronectin with PAI-1. The structure of the complex explains how vitronectin binds to and stabilizes the active conformation of PAI-1. It also explains the tissue effects of PAI-1, as PAI-1 competes for and sterically blocks the interaction of vitronectin with cell surface receptors and integrins. Structural understanding of the essential biological roles of the interaction between PAI-1 and vitronectin opens the prospect of specifically designed blocking agents for the prevention of thrombosis and treatment of cancer.

Selected figure(s)

Figure 1.
Figure 1. Ribbon diagrams of the complex and its components. (a) Latent PAI-1 (ref. 9). In this structure, the reactive center loop is inserted as strand 4 (red) of an expanded sheet A (cyan), changing the shape of the binding site (yellow) for somatomedin B. (b) The somatomedin B domain (gray with pink disulfide bridges) binding to the region comprising helix E, strand 1A and helix F (green) of active PAI-1. Dashed lines indicate disordered residues in the reactive center loop (RCL) of PAI-1 and residues leading to the RGD sequence of somatomedin B. (c) The somatomedin B domain (blue at N terminus to red at C terminus), showing disulfide bridges (pink) and side chains of residues that interact with PAI-1. The sequence highlights disulfide bridges (brackets), residues conserved among mammalian vitronectin sequences (bold italic), residues with side chains contacting PAI-1 (red) and the RGD motif (blue). (d) Comparison of the active (green) and latent (yellow) conformations of PAI-1 showing how the shape of the binding surface changes upon latency.

Figure 2.
Figure 2. Stereo view of interacting residues in the PAI-1 -SMB interface. (a) The region of the somatomedin B domain that interacts with PAI-1 overlaps extensively with that involved in the interaction with uPAR, as alanine-scanning mutagenesis has shown that residues Asp22, Glu23, Leu24, Tyr27 and Tyr28 of vitronectin (highlighted with magenta bonds) are important for the interaction with uPAR16. Somatomedin B coloring ranges from blue at the N terminus to red at the C terminus. (b) Electron density from the final [A]-weighted^26 map showing the interaction between helix F (hF) of PAI-1 (gray bonds) and the loop comprising residues 23 -28 of SMB (pink bonds). The map is contoured at a level of 1.25 the r.m.s. electron density. For clarity, contours >2 Å from an atom in the figure are omitted.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2003, 10, 541-544) copyright 2003.