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PDBsum entry 4g8o
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Blood clotting/inhibitor
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PDB id
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4g8o
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References listed in PDB file
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Key reference
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Title
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Mechanistic characterization and crystal structure of a small molecule inactivator bound to plasminogen activator inhibitor-1.
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Authors
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S.H.Li,
A.A.Reinke,
K.L.Sanders,
C.D.Emal,
J.C.Whisstock,
J.A.Stuckey,
D.A.Lawrence.
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Ref.
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Proc Natl Acad Sci U S A, 2013,
110,
E4941.
[DOI no: ]
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PubMed id
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Abstract
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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.
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