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PDBsum entry 3f1s
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Hydrolase inhibitor/hydrolase
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PDB id
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3f1s
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References listed in PDB file
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Key reference
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Title
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Crystal structure of protein z-Dependent inhibitor complex shows how protein z functions as a cofactor in the membrane inhibition of factor x.
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Authors
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Z.Wei,
Y.Yan,
R.W.Carrell,
A.Zhou.
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Ref.
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Blood, 2009,
114,
3662-3667.
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PubMed id
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Abstract
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Protein Z (PZ) binds to PZ-dependent inhibitor (ZPI) and accelerates the
inhibition of the coagulation protease, activated factor X (FXa), in the
presence of phospholipids and Ca2+. A 2.3A resolution crystal structure of PZ
complexed with ZPI shows that ZPI is a typical serine protease inhibitor and
that PZ has a serine protease fold with distorted oxyanion hole and S1 pocket.
The 2 molecules bind with fully complementary surfaces spanning over 2400A(2)
and involving extensive ionic and hydrophobic interactions. ZPI has an unusual
shutter region with a negatively charged residue buried within the hydrophobic
core of the molecule. This unique Asp(213) is critical in maintaining the
balanced metastability required for optimal protease inhibition, especially when
PZ is bound, with its replacement with Asn resulting in increased thermal
stability, but decreased efficiency of protease inhibition. The structure of ZPI
shows negatively and positively charged surfaces on top of the molecule, in
keeping with mutagenesis studies in this work indicating exosite interactions
with FXa when it docks on top of ZPI. As modeled in this study, the
gamma-carboxy-glutamic acid-containing domains of PZ and FXa enable them to bind
to the same phospholipid surfaces on platelet and other membranes, with optimal
proximity for the inhibition of FXa by the complexed ZPI.
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