5io1: Difference between revisions
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<table><tr><td colspan='2'>[[5io1]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IO1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5IO1 FirstGlance]. <br> | <table><tr><td colspan='2'>[[5io1]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IO1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5IO1 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5io1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5io1 OCA], [http://pdbe.org/5io1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5io1 RCSB], [http://www.ebi.ac.uk/pdbsum/5io1 PDBsum]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5io1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5io1 OCA], [http://pdbe.org/5io1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5io1 RCSB], [http://www.ebi.ac.uk/pdbsum/5io1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5io1 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == Disease == | ||
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== Function == | == Function == | ||
[[http://www.uniprot.org/uniprot/A1AT_HUMAN A1AT_HUMAN]] Inhibitor of serine proteases. Its primary target is elastase, but it also has a moderate affinity for plasmin and thrombin. Irreversibly inhibits trypsin, chymotrypsin and plasminogen activator. The aberrant form inhibits insulin-induced NO synthesis in platelets, decreases coagulation time and has proteolytic activity against insulin and plasmin.[:]<ref>PMID:1906855</ref> <ref>PMID:1406456</ref> Short peptide from AAT: reversible chymotrypsin inhibitor. It also inhibits elastase, but not trypsin. Its major physiological function is the protection of the lower respiratory tract against proteolytic destruction by human leukocyte elastase (HLE).[:]<ref>PMID:1906855</ref> <ref>PMID:1406456</ref> | [[http://www.uniprot.org/uniprot/A1AT_HUMAN A1AT_HUMAN]] Inhibitor of serine proteases. Its primary target is elastase, but it also has a moderate affinity for plasmin and thrombin. Irreversibly inhibits trypsin, chymotrypsin and plasminogen activator. The aberrant form inhibits insulin-induced NO synthesis in platelets, decreases coagulation time and has proteolytic activity against insulin and plasmin.[:]<ref>PMID:1906855</ref> <ref>PMID:1406456</ref> Short peptide from AAT: reversible chymotrypsin inhibitor. It also inhibits elastase, but not trypsin. Its major physiological function is the protection of the lower respiratory tract against proteolytic destruction by human leukocyte elastase (HLE).[:]<ref>PMID:1906855</ref> <ref>PMID:1406456</ref> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The Z mutation (E342K) of alpha1-antitrypsin (alpha1-AT), carried by 4% of Northern Europeans, predisposes to early onset of emphysema due to decreased functional alpha1-AT in the lung and to liver cirrhosis due to accumulation of polymers in hepatocytes. However, it remains unclear why the Z mutation causes intracellular polymerization of nascent Z alpha1-AT and why 15% of the expressed Z alpha1-AT is secreted into circulation as functional, but polymerogenic, monomers. Here, we solve the crystal structure of the Z-monomer and have engineered replacements to assess the conformational role of residue Glu-342 in alpha1-AT. The results reveal that Z alpha1-AT has a labile strand 5 of the central beta-sheet A (s5A) with a consequent equilibrium between a native inhibitory conformation, as in its crystal structure here, and an aberrant conformation with s5A only partially incorporated into the central beta-sheet. This aberrant conformation, induced by the loss of interactions from the Glu-342 side chain, explains why Z alpha1-AT is prone to polymerization and readily binds to a 6-mer peptide, and it supports that annealing of s5A into the central beta-sheet is a crucial step in the serpins' metastable conformational formation. The demonstration that the aberrant conformation can be rectified through stabilization of the labile s5A by binding of a small molecule opens a potential therapeutic approach for Z alpha1-AT deficiency. | |||
Molecular Mechanism of Z alpha1-Antitrypsin Deficiency.,Huang X, Zheng Y, Zhang F, Wei Z, Wang Y, Carrell RW, Read RJ, Chen GQ, Zhou A J Biol Chem. 2016 Jul 22;291(30):15674-86. doi: 10.1074/jbc.M116.727826. Epub, 2016 May 31. PMID:27246852<ref>PMID:27246852</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
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<div class="pdbe-citations 5io1" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Alpha-1-antitrypsin|Alpha-1-antitrypsin]] | |||
== References == | == References == | ||
<references/> | <references/> | ||