Mechanisms contributing to the conformational and functional flexibility of plasminogen activator inhibitor-1.
Plasminogen activator inhibitor-1 (PAI-1) is unique among the serine proteinase inhibitors (serpins) in that it can adopt at least three different conformations (active, substrate and latent). We report the X-ray structure of a cleaved substrate variant of human PAI-1, which has a new beta-strand s4A formed by insertion of the amino-terminal portion of the reactive-site loop into beta-sheet A subsequent to cleavage. This is in contrast to the previous suggestion that the non-inhibitory function of substrate-type serpins is mainly due to an inability of the reactive-site loop to adopt this conformation. Comparison with the structure of latent PAI-1 provides insights into the molecular determinants responsible for the transition of the stressed active conformation to the thermostable latent conformation.
Aertgeerts
K
K
Laboratory for Analytical Chemistry and Medicinal Physicochemistry, Faculty of Pharmaceutical Sciences, Katholieke Universiteit Leuven, Belgium.
De Bondt
H L
HL
De Ranter
C J
CJ
Declerck
P J
PJ
D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017395:Plasminogen Activator Inhibitor 1 / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D011487:Protein Conformation; D016415:Sequence Alignment; D015842:Serine Proteinase Inhibitors / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D017395:Plasminogen Activator Inhibitor 1; D015842:Serine Proteinase Inhibitors