3ne4: Difference between revisions
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The | ==1.8 Angstrom structure of intact native wild-type alpha-1-antitrypsin== | ||
<StructureSection load='3ne4' size='340' side='right'caption='[[3ne4]], [[Resolution|resolution]] 1.81Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3ne4]] is a 1 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=3NE4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3NE4 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]] 1.81Å</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=3ne4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ne4 OCA], [https://pdbe.org/3ne4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ne4 RCSB], [https://www.ebi.ac.uk/pdbsum/3ne4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ne4 ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/A1AT_HUMAN A1AT_HUMAN] Defects in SERPINA1 are the cause of alpha-1-antitrypsin deficiency (A1ATD) [MIM:[https://omim.org/entry/613490 613490]. A disorder whose most common manifestation is emphysema, which becomes evident by the third to fourth decade. A less common manifestation of the deficiency is liver disease, which occurs in children and adults, and may result in cirrhosis and liver failure. Environmental factors, particularly cigarette smoking, greatly increase the risk of emphysema at an earlier age.<ref>PMID:1905728</ref> <ref>PMID:2390072</ref> <ref>PMID:2227940</ref> | |||
== Function == | |||
[https://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 intrinsic propensity of alpha(1)-antitrypsin to undergo conformational transitions from its metastable native state to hyperstable forms provides a motive force for its antiprotease function. However, aberrant conformational change can also occur via an intermolecular linkage that results in polymerization. This has both loss-of-function and gain-of-function effects that lead to deficiency of the protein in human circulation, emphysema and hepatic cirrhosis. One of the most promising therapeutic strategies being developed to treat this disease targets small molecules to an allosteric site in the alpha(1)-antitrypsin molecule. Partial filling of this site impedes polymerization without abolishing function. Drug development can be improved by optimizing data on the structure and dynamics of this site. A new 1.8 A resolution structure of alpha(1)-antitrypsin demonstrates structural variability within this site, with associated fluctuations in its upper and lower entrance grooves and ligand-binding characteristics around the innermost stable enclosed hydrophobic recess. These data will allow a broader selection of chemotypes and derivatives to be tested in silico and in vitro when screening and developing compounds to modulate conformational change to block the pathological mechanism while preserving function. | |||
Therapeutic target-site variability in alpha(1)-antitrypsin characterized at high resolution.,Patschull AO, Segu L, Nyon MP, Lomas DA, Nobeli I, Barrett TE, Gooptu B Acta Crystallogr Sect F Struct Biol Cryst Commun. 2011 Dec 1;67(Pt, 12):1492-7. Epub 2011 Nov 25. PMID:22139150<ref>PMID:22139150</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3ne4" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Alpha-1-antitrypsin 3D structures|Alpha-1-antitrypsin 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Gooptu B]] | |||
[[Category: Patschull AOM]] | |||
[[Category: Segu L]] | |||