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==Human plasminogen activator inhibitor-2.[loop (66-98) deletion mutant] complexed with peptide n-acetyl-teaaagdggvmtgr-oh== | |||
<StructureSection load='2arq' size='340' side='right'caption='[[2arq]], [[Resolution|resolution]] 1.85Å' scene=''> | |||
| | == Structural highlights == | ||
<table><tr><td colspan='2'>[[2arq]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ARQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2ARQ FirstGlance]. <br> | |||
| | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.85Å</td></tr> | ||
| | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2arq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2arq OCA], [https://pdbe.org/2arq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2arq RCSB], [https://www.ebi.ac.uk/pdbsum/2arq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2arq ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/PAI2_HUMAN PAI2_HUMAN] Inhibits urokinase-type plasminogen activator. The monocyte derived PAI-2 is distinct from the endothelial cell-derived PAI-1. | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ar/2arq_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2arq ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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. | |||
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<ref>PMID:16214170</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2arq" style="background-color:#fffaf0;"></div> | |||
== | ==See Also== | ||
*[[Plasminogen activator inhibitor|Plasminogen activator inhibitor]] | |||
== References == | |||
== | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Curmi | [[Category: Curmi PM]] | ||
[[Category: Giusto | [[Category: Di Giusto DA]] | ||
[[Category: Harrop | [[Category: Harrop SJ]] | ||
[[Category: Jankova | [[Category: Jankova L]] | ||
[[Category: King | [[Category: King GC]] | ||
[[Category: Sutherland | [[Category: Sutherland AP]] | ||
Latest revision as of 10:50, 30 October 2024
Human plasminogen activator inhibitor-2.[loop (66-98) deletion mutant] complexed with peptide n-acetyl-teaaagdggvmtgr-ohHuman plasminogen activator inhibitor-2.[loop (66-98) deletion mutant] complexed with peptide n-acetyl-teaaagdggvmtgr-oh
Structural highlights
FunctionPAI2_HUMAN Inhibits urokinase-type plasminogen activator. The monocyte derived PAI-2 is distinct from the endothelial cell-derived PAI-1. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe 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. 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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