View source for 6hgg


==Crystal structure of Alpha1-antichymotrypsin variant NewBG-III: a new binding globulin in complex with cortisol==
<StructureSection load='6hgg' size='340' side='right'caption='[[6hgg]], [[Resolution|resolution]] 1.79&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6hgg]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6HGG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6HGG FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=HCY:(11ALPHA,14BETA)-11,17,21-TRIHYDROXYPREGN-4-ENE-3,20-DIONE'>HCY</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SERPINA3, AACT, GIG24, GIG25 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6hgg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hgg OCA], [http://pdbe.org/6hgg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6hgg RCSB], [http://www.ebi.ac.uk/pdbsum/6hgg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6hgg ProSAT]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/AACT_HUMAN AACT_HUMAN]] Although its physiological function is unclear, it can inhibit neutrophil cathepsin G and mast cell chymase, both of which can convert angiotensin-1 to the active angiotensin-2.<ref>PMID:2404007</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The introduction of ligand-binding sites into proteins and the engineering of molecular allosteric coupling pathways are topical issues in protein design. Here, we show that these issues can be addressed concurrently, using the serpin human alpha1-antichymotrypsin (ACT) as a model. We have introduced up to 15 amino acid substitutions into ACT, converting it into a surrogate corticosteroid-binding globulin (CBG), thereby creating a new binding globulin (NewBG). Human CBG and ACT share 46% sequence identity, and CBG served as the blue-print for our design, which was guided by side-chain-packing calculations, ITC measurements and crystal structure determinations. Upon transfer of ligand-interacting residues from CBG to ACT and mutation of specific second shell residues, a NewBG variant was obtained, which binds cortisol with 1.5microM affinity. This novel serpin (NewBG-III) binds cortisol with a 33-fold lower affinity than CBG, but shares a similar ligand-binding profile and binding mode when probed with different steroid ligands and site-directed mutagenesis. An additional substitution, i.e. A349R, created NewBG-III-allo, which introduced an allosteric coupling between ligand binding and the serpin-like S-to-R transition in ACT. In NewBG-III-allo, the proteinase-triggered S-to-R transition leads to a greater than 200-fold reduction in ligand affinity, and crystal structures suggest that this is mediated by the L55V and A349R substitutions. This reduction significantly exceeds the 10-fold reduction in binding affinity observed in human CBG.

NewBG: A surrogate corticosteroid-binding globulin with an unprecedentedly high ligand release efficacy.,Gardill BR, Schmidt K, Muller YA J Struct Biol. 2019 May 16. pii: S1047-8477(19)30110-8. doi:, 10.1016/j.jsb.2019.05.006. PMID:31103428<ref>PMID:31103428</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6hgg" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Muller, Y A]]
[[Category: Schmidt, K]]
[[Category: Alpha1-antichymotrypsin]]
[[Category: Computational protein design]]
[[Category: Serpin]]
[[Category: Transport protein]]