View source for 4qgt


==The Crystal Structure of Human IgG Fc Domain with Enhanced Aromatic Sequon==
<StructureSection load='4qgt' size='340' side='right'caption='[[4qgt]], [[Resolution|resolution]] 2.99&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4qgt]] 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=4QGT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4QGT 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]] 2.99&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <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'>[https://proteopedia.org/fgij/fg.htm?mol=4qgt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qgt OCA], [https://pdbe.org/4qgt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4qgt RCSB], [https://www.ebi.ac.uk/pdbsum/4qgt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4qgt ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q6PYX1_HUMAN Q6PYX1_HUMAN] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Monoclonal antibodies (mAbs) exhibiting highly selective binding to a protein target constitute a large and growing proportion of the therapeutics market. Aggregation of mAbs results in the loss of their therapeutic efficacy and can result in deleterious immune responses. The CH2 domain comprising part of the Fc portion of Immunoglobulin G (IgG) is typically the least stable domain in IgG-type antibodies and therefore influences their aggregation propensity. We stabilized the CH2 domain by engineering an enhanced aromatic sequon (EAS) into the N-glycosylated C'E loop and observed a 4.8 degrees C increase in the melting temperature of the purified IgG1 Fc fragment. This EAS-stabilized CH2 domain also conferred enhanced stability against thermal and low pH induced aggregation in the context of a full-length monoclonal IgG1 antibody. The crystal structure of the EAS-stabilized (Q295F/Y296A) IgG1 Fc fragment confirms the design principle, i.e., the importance of the GlcNAc1*F295 interaction, and surprisingly reveals that the core fucose attached to GlcNAc1 also engages in an interaction with F295. Inhibition of core fucosylation confirms the contribution of the fucose-Phe interaction to the stabilization. The Q295F/Y296A mutations also modulate the binding affinity of the full-length antibody to Fc receptors by decreasing the binding to low affinity Fc gamma receptors (FcgammaRIIa, FcgammaRIIIa, and FcgammaRIIIb), while maintaining wild-type binding affinity to FcRn and FcgammaRI. Our results demonstrate that engineering an EAS into the N-glycosylated reverse turn on the C'E loop leads to stabilizing N-glycan-protein interactions in antibodies and that this modification modulates antibody-Fc receptor binding.

Stabilizing the CH2 Domain of an Antibody by Engineering in an Enhanced Aromatic Sequon.,Chen W, Kong L, Connelly S, Dendle JM, Liu Y, Wilson IA, Powers ET, Kelly JW ACS Chem Biol. 2016 Jul 15;11(7):1852-61. doi: 10.1021/acschembio.5b01035. Epub, 2016 Apr 29. PMID:27128252<ref>PMID:27128252</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4qgt" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Connelly SC]]
[[Category: Kong L]]
[[Category: Wilson IA]]