2arr
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Human plasminogen activator inhibitor-2.[loop (66-98) deletion mutant] complexed with peptide n-acetyl-teaaagmggvmtgr-oh
OverviewOverview
The serine protease inhibitor (serpin) superfamily is involved in a wide, range of cellular processes including fibrinolysis, angiogenesis, apoptosis, inflammation, metastasis and viral pathogenesis. Here, we, investigate the unique mousetrap inhibition mechanism of serpins through, saturation mutagenesis of the P8 residue for a typical family member, plasminogen activator inhibitor-2 (PAI-2). A number of studies have, proposed an important role for the P8 residue in the efficient insertion, and stabilisation of the cleaved reactive centre loop (RCL), which is a, key event in the serpin inhibitory mechanism. The importance of this, residue for inhibition of the PAI-2 protease target urinary plasminogen, activator (urokinase, uPA) is confirmed, although a high degree of, tolerance to P8 substitution is observed. Out of 19 possible PAI-2 P8, mutants, 16 display inhibitory activities within an order of magnitude of, the wild-type P8 Thr species. Crystal structures of complexes between, PAI-2 and RCL-mimicking peptides with P8 Met or Asp mutations are, determined, and structural comparison with the wild-type complex, substantiates the ability of the S8 pocket to accommodate disparate, side-chains. These data indicate that the identity of the P8 residue is, not a determinant of efficient RCL insertion, and provide further evidence, for functional plasticity of key residues within enzyme structures. Poor, correlation of observed PAI-2 P8 mutant activities with a range of, physicochemical, evolutionary and thermodynamic predictive indices, highlights the practical limitations of existing approaches to predicting, the molecular phenotype of protein variants.
About this StructureAbout this Structure
2ARR is a Protein complex structure of sequences from Homo sapiens with ACE as ligand. Full crystallographic information is available from OCA.
ReferenceReference
Plasminogen activator inhibitor-2 is highly tolerant to P8 residue substitution--implications for serpin mechanistic model and prediction of nsSNP activities., Di Giusto DA, Sutherland AP, Jankova L, Harrop SJ, Curmi PM, King GC, J Mol Biol. 2005 Nov 11;353(5):1069-80. Epub 2005 Sep 22. PMID:16214170
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