View source for 6tkb


==ChiLob 7/4 H2 HC-C224S F(ab')2==
<StructureSection load='6tkb' size='340' side='right'caption='[[6tkb]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6tkb]] is a 4 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=6TKB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TKB 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&#8491;</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=6tkb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tkb OCA], [https://pdbe.org/6tkb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6tkb RCSB], [https://www.ebi.ac.uk/pdbsum/6tkb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6tkb ProSAT]</span></td></tr>
</table>
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== Publication Abstract from PubMed ==
Antibodies protect from infection, underpin successful vaccines and elicit therapeutic responses in otherwise untreatable cancers and autoimmune conditions. The human IgG2 isotype displays a unique capacity to undergo disulfide shuffling in the hinge region, leading to modulation of its ability to drive target receptor signaling (agonism) in a variety of important immune receptors, through hitherto unexplained molecular mechanisms. To address the underlying process and reveal how hinge disulfide orientation affects agonistic activity, we generated a series of cysteine to serine exchange variants in the hinge region of the clinically relevant monoclonal antibody ChiLob7/4, directed against the key immune receptor CD40. We report how agonistic activity varies with disulfide pattern and is afforded by the presence of a disulfide crossover between F(ab) arms in the agonistic forms, independently of epitope, as observed in the determined crystallographic structures. This structural "switch" affects directly on antibody conformation and flexibility. Small-angle x-ray scattering and ensemble modeling demonstrated that the least flexible variants adopt the fewest conformations and evoke the highest levels of receptor agonism. This covalent change may be amenable for broad implementation to modulate receptor signaling in an epitope-independent manner in future therapeutics.

Hinge disulfides in human IgG2 CD40 antibodies modulate receptor signaling by regulation of conformation and flexibility.,Orr CM, Fisher H, Yu X, Chan CH, Gao Y, Duriez PJ, Booth SG, Elliott I, Inzhelevskaya T, Mockridge I, Penfold CA, Wagner A, Glennie MJ, White AL, Essex JW, Pearson AR, Cragg MS, Tews I Sci Immunol. 2022 Jul 15;7(73):eabm3723. doi: 10.1126/sciimmunol.abm3723. Epub , 2022 Jul 8. PMID:35857577<ref>PMID:35857577</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Fisher H]]
[[Category: Orr CM]]
[[Category: Tews I]]